Compositions with a rheological modifier to reduce dissolution variability

ABSTRACT

The present disclosure provides compositions (e.g., extended release compositions) which exhibit a desirable pharmacokinetic profile of an active agent while providing reduced dissolution sample variability, e.g., in the form of reduced inter-capsule variability and/or a reduction in storage-time dependent change in mean release of the active agent from the composition. Related methods of making and administering the disclosed compositions are also provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/776,585, filed Sep. 14, 2015, now U.S. Pat. No. 9,572,885, whichapplication is a national stage entry of International PatentApplication No. PCT/US2014/029607, filed Mar. 14, 2014, whichapplication claims the benefit of and expressly incorporates byreference herein the entire disclosure of U.S. Provisional PatentApplication No. 61/801,110, filed Mar. 15, 2013.

INTRODUCTION

Extended release pharmaceutical compositions, including extended releaseoxycodone compositions, may include various pharmaceutically inactivecomponents which contribute to the desired pharmacokinetic parameters ofthe active agent in the composition. Such compositions may also includepharmaceutically inactive components which contribute to one or moreabuse-deterrent characteristics of the composition. In some such cases,extended release pharmaceutical compositions may be provided which areviscoelastic in nature with a combination of hydrophilic and hydrophobiccomponents. In addition to solubility of the active agent in thecomposition, the release of the active agent may be controlled, at leastin part, by balancing the viscoelastic, hydrophilic and/or hydrophobicnature of the composition. However, in some cases, the viscoelastic,hydrophilic, and/or hydrophobic nature of the composition may alsocontribute to undesirable sample variability during dissolution of theactive agent from the composition. This undesirable sample variabilitymay be evidenced by inter-capsule variability at a particular time pointand/or as a storage-time dependent change in mean release of the activeagent from the composition (aging). The present disclosure addressesthese issues and provides related advantages.

SUMMARY

The present disclosure provides compositions (e.g., extended releasecompositions) which exhibit a desirable pharmacokinetic profile of anactive agent while providing reduced dissolution sample variability,e.g., in the form of reduced inter-capsule variability and/or areduction in storage-time dependent change in mean release of the activeagent from the composition. Related methods of making and administeringthe disclosed compositions are also provided.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a graph showing a storage-time dependent change in therelease of oxycodone from a reference composition (Reference FormulationA (with BHT)).

FIG. 1B provides graphs showing the effect of formulating ReferenceFormulation A in gelatin (Panel A) vs. HPMC (Panel B) capsules.

FIG. 1C provides a graph showing comparative plots of Formulation A(without BHT) in gelatin and HPMC capsules. The results of two separatetests are shown.

FIG. 1D provides a graph showing the variation of gelatin and HPMC lotsusing Type 3 dissolution. The results of two separate tests are shown.

FIG. 2 shows a flow diagram of an exemplary composition preparation andencapsulation method.

FIG. 3 is a graph showing mean plasma oxycodone concentration profilesfollowing administration of Reference Formulation A (without BHT) andFormulations 1-3.

FIG. 4 is a graph showing mean plasma oxycodone concentration profilesfollowing administration of Reference Formulation A (without BHT) andFormulations 4-7 and Formulation 5^(a).

FIG. 5 is a graph showing mean plasma oxycodone concentration profilesfollowing administration of Reference Formulation A (without BHT) andFormulations 8 and 9.

FIG. 6 provides graphs showing the results of in vitro dissolutionexperiments for Reference Formulation A (with BHT) (Panel A) andFormulations 10 (Panel B) and 11 (Panel C).

FIG. 7 provides graphs showing the results of in vitro dissolutionexperiments for Reference Formulation A (with BHT) (Panel A) andFormulations 12 (Panel B) and 13 (Panel C).

FIG. 8 provides graphs showing the effects of IPM (Panel A) and SiO₂(Panel B) on mean release of oxycodone relative to Reference FormulationA (with BHT).

FIG. 9 is a graph showing the effect of SiO₂ on an oxycodone meanrelease profile. Results for Formulation 1, and Formulations 14 and 15are shown.

FIG. 10 provides graphs showing the effect of increased amounts of SiO₂on inter-capsule variability during dissolution. Results for Formulation1 (Panel A), and Formulations 14 (Panel B) and 15 (Panel C) are shown.

FIG. 11 is a graph showing the complex viscosity profiles forFormulations 1, 14 and 15. Increasing SiO₂ concentration above about 2%increases complex viscosity which may lead to decreasing reproducibledeformation and therefore low inter-capsule variability duringdissolution testing.

FIG. 12 is a graph showing mean release of oxycodone from Formulation 1following storage for 1 month at 25° C. or 40° C.

FIG. 13 provides graphs showing inter-capsule variability duringdissolution testing of Formulation 1 following storage for 1 month at25° C. or 40° C.

FIG. 14 is a graph showing mean release of oxycodone from Formulation 14following storage for 1 month at 25° C. or 40° C.

FIG. 15 provides graphs showing inter-capsule variability duringdissolution testing of Formulation 14 following storage for 1 month at25° C. or 40° C.

FIG. 16 is a graph showing mean release of oxycodone from Formulation 15following storage for 1 month at 25° C. or 40° C.

FIG. 17 provides graphs showing inter-capsule variability duringdissolution testing of Formulation 15 following storage for 1 month at25° C. or 40° C.

FIG. 18 is a graph showing mean release of oxycodone from Formulations16, 17 and 18.

FIG. 19 provides graphs showing inter-capsule variability duringdissolution testing of Formulation 16 (Panel A), Formulation 17 (PanelB) and Formulation 18 (Panel C).

FIG. 20 is a graph showing mean release of oxycodone from Formulation 16following storage for 1 month at 25° C. or 40° C.

FIG. 21 provides graphs showing inter-capsule variability duringdissolution testing of Formulation 16 following storage for 1 month at25° C. or 40° C.

FIG. 22 is a graph showing mean release of oxycodone from Formulation 17following storage for 1 month at 25° C. or 40° C.

FIG. 23 provides graphs showing inter-capsule variability duringdissolution testing of Formulation 17 following storage for 1 month at25° C. or 40° C.

FIG. 24 is a graph showing mean release of oxycodone from Formulation 18following storage for 1 month at 25° C. or 40° C.

FIG. 25 provides graphs showing inter-capsule variability duringdissolution testing of Formulation 18 following storage for 1 month at25° C. or 40° C.

FIG. 26 is a graph showing mean release of oxycodone from Formulations5, 7, 9, 19 and 20, with varying levels of SiO₂ and 5 mg oxycodone.

FIG. 27 provides graphs showing inter-capsule variability duringdissolution testing of Formulations 5 (Panel A), 7 (Panel E), 9 (PanelC), 19 (Panel B) and 20 (Panel D), with varying levels of SiO₂ and 5 mgoxycodone.

FIG. 28 is a graph showing mean release of oxycodone from Formulations5, 7, 9, 19 and 20, with varying levels of SiO₂ and 40 mg oxycodone.

FIG. 29 provides graphs showing inter-capsule variability duringdissolution testing of Formulations 5 (Panel A), 7 (Panel E), 9 (PanelC), 19 (Panel B) and 20 (Panel D), with varying levels of SiO₂ and 40 mgoxycodone.

FIG. 30 is a graph showing complex viscosity as a function oftemperature for Reference Formulation A and Formulations 5, 7, 9, 19 and20.

FIG. 31 is another graph showing complex viscosity as a function oftemperature for Reference Formulation A and Formulations 5, 7, 9, 19 and20. The graph in FIG. 31 provides a different temperature scale thanthat for FIG. 30.

FIG. 32 is a graph showing storage modulus (G′) as a function oftemperature for Reference Formulation A and Formulations 5, 7, 9, 19 and20.

FIG. 33 is a graph showing loss modulus (G″) as a function oftemperature for Reference Formulation A and Formulations 5, 7, 9, 19 and20.

FIG. 34 is a graph showing damping factor (G″/G′) as a function oftemperature for Reference Formulation A and Formulations 5, 7, 9, 19 and20.

FIG. 35 provides graphs showing complex viscosity (Panel A) and storagemodulus (Panel B) as a function of SiO₂ content at temperatures betweenabout 50 and 70° C. based on the results for Formulations 5, 7, 9, 19and 20.

FIG. 36 provides graphs showing loss modulus (Panel A) and dampingfactor (Panel B) as a function of SiO₂ content at temperatures betweenabout 50 and 70° C. based on the results for Formulations 5, 7, 9, 19and 20.

FIG. 37 is a graph showing mean release for Formulation 5 (40 mg)following storage at 25° C./60% relative humidity (RH) and 40° C./75% RHfor up to 6 months.

FIG. 38 is a graph showing mean release for Formulation 8 (40 mg)following storage for 1 month at 40° C./75% RH or 2 months at 25° C./60%RH.

FIG. 39 is a graph showing mean release for Formulation 9 (40 mg)following storage for 1 month at 40° C./75% RH or 2 months at 25° C./60%RH.

FIG. 40 is a graph showing mean release for Formulation 7 (40 mg)following storage for 1 month at 40° C./75% RH or 3 months at 25° C./60%RH or 40° C./75% RH.

FIG. 41 is a graph showing cumulative release of hydromorphone HCl forselected formulations over time.

FIG. 42 is a graph showing the % cumulative amount of hydromorphone HClreleased over time under abuse extraction conditions.

FIG. 43 is a flow chart providing materials and methods for thepreparation of selected hydromorphone HCl compositions.

FIG. 44 is a graph showing initial dissolution results (TO) for selectformulations in gelatin and HPMC capsules.

FIG. 45 is a graph showing cumulative % drug release over time for aformulation in hard gelatin capsules with storage conditions of 1 monthat 25° C. and 40° C., or 30 months at 25° C.

FIG. 46 is a graph showing cumulative % drug release over time for theformulation of FIG. 45 in HPMC capsules with storage conditions of 1month at 25° C. and 40° C., or 30 months at 25° C.

FIG. 47 is a graph showing cumulative % drug release over time for aformulation in hard gelatin capsules with storage conditions of 1 monthat 25° C. and 40° C., or 30 months at 25° C.

FIG. 48 is a graph showing cumulative % drug release over time for theformulation of FIG. 47 in HPMC capsules with storage conditions of 1month at 25° C. and 40° C., or 30 months at 25° C.

DEFINITIONS

As used interchangeably herein, the terms “active agent”,“pharmacologically active agent” and “beneficial agent” refer to anysubstance intended for use in the diagnosis, cure, mitigation,treatment, or prevention of any disease, disorder, or condition orintended to affect the structure or function of the body, other thanfood. It can include any beneficial agent or substance that isbiologically active or meant to alter animal physiology.

As used herein, the term “high viscosity liquid carrier material(HVLCM)” refers to a non-polymeric, non-water soluble liquid materialhaving a viscosity of at least 5000 cP at 37° C. that does notcrystallize neat at 25° C. and 1 atmosphere.

As used herein, the term “rheology modifier” refers to a substance thatpossesses both a hydrophobic and a hydrophilic moiety. Rheologymodifiers suitable for use in the disclosed compositions and methodsgenerally have a logarithm of octanol-water partition coefficient (“LogP”) of between about −7 and +15, e.g., between −5 and +10, e.g., between−1 and +7.

As used herein, the term “network former” refers to a material orcompound that forms a network structure when introduced into a liquidmedium (such as a HVLCM).

As used herein, the term “hydrophilic agent” means a compound ormaterial having a natural affinity for aqueous systems. A material maybe regarded as a hydrophilic agent for the purposes of this disclosureif the material displays a water sorption between about 10 to 100%(w/w). Hydrophilic agents will have a low Log P value, for example, aLog P of less than +1.

As used herein, the term “hydrophilic solvent” means a solvent meetingthe definition of a hydrophilic agent as described above.

The term “solvent”, as used herein, refers to any substance thatdissolves another substance (solute).

As used herein, the term “treatment”, “treat” and “treating” pain refersto eliminating, reducing, suppressing or ameliorating, eithertemporarily or permanently, either partially or completely, a clinicalsymptom, manifestation or progression of pain. In addition, oralternatively, the terms “treatment”, “treat” and “treating” as usedherein with respect to the methods as described refer to inhibiting,delaying, suppressing, reducing, eliminating or ameliorating, eithertemporarily or permanently, either partially or completely, pain. Insome embodiments the treating is effective to reduce a symptom, sign,and/or condition of pain in a subject by at least about 10% (e.g., 15%,20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, or 100%) including, as compared to a baseline measurement ofthe symptom, sign, and/or condition made prior to the treatment. In someembodiments, the treating is effective to improve an assessment used todiagnose pain in a subject including, as compared to a baselineassessment made prior to the treatment. Such treating as provided hereinneed not be absolute to be useful.

The term “pharmaceutically acceptable salt,” as used herein, intendsthose salts that retain the biological effectiveness and properties ofneutral active agents and are not otherwise unacceptable forpharmaceutical use.

As used herein, the term “viscosity enhancing agent” refers to acompound or material that can be added to an extended releasecomposition in order to increase the viscosity of the resultingcomposition.

As used herein, the term “stabilizer” refers to any substance used toinhibit or reduce degradation (e.g., chemical) of other substances withwhich the stabilizer is mixed.

The terms “% w/w” and “w %” are used interchangeably herein to refer topercent weight per weight.

Before the present invention is further described, it is to beunderstood that this invention is not limited to particular embodimentsdescribed, as such may, of course, vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to be limiting, sincethe scope of the present invention will be limited only by the appendedclaims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the invention. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges, and are also encompassed within the invention, subjectto any specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either orboth of those included limits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, exemplarymethods and materials are now described. All publications mentionedherein are incorporated herein by reference to disclose and describe themethods and/or materials in connection with which the publications arecited.

It must be noted that as used herein and in the appended claims, thesingular forms “a,” “and,” and “the” include plural referents unless thecontext clearly dictates otherwise. Thus, for example, reference to “acomposition” includes a plurality of such compositions and reference to“the capsule” includes reference to one or more capsules and equivalentsthereof known to those skilled in the art, and so forth. It is furthernoted that the claims may be drafted to exclude any element, e.g., anyoptional element. As such, this statement is intended to serve asantecedent basis for use of such exclusive terminology as “solely,”“only” and the like in connection with the recitation of claim elements,or use of a “negative” limitation.

To the extent the definition or usage of any term herein conflicts witha definition or usage of a term in an application or referenceincorporated by reference herein, the instant application shall control.

The publications discussed herein are provided solely for theirdisclosure prior to the filing date of the present application. Nothingherein is to be construed as an admission that the present invention isnot entitled to antedate such publication by virtue of prior invention.Further, the dates of publication provided may be different from theactual publication dates which may need to be independently confirmed.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentinvention. Any recited method can be carried out in the order of eventsrecited or in any other order which is logically possible. This isintended to provide support for all such combinations.

DETAILED DESCRIPTION

As discussed previously herein, the viscoelastic, hydrophilic and/orhydrophobic nature of a pharmaceutical composition may contribute toundesirable sample variability during dissolution of the active agentfrom the composition. This undesirable sample variability may beevidenced by inter-capsule variability at a particular time point and/oras a storage-time dependent change in mean release of the active agentfrom the composition.

The present disclosure provides compositions (e.g., extended releasecompositions) which exhibit a desirable pharmacokinetic profile of anactive agent while providing reduced dissolution sample variability,e.g., in the form of reduced in vitro inter-capsule variability and/or areduction in storage-time dependent change in mean in vitro release ofthe active agent from the composition. Related methods of making andadministering the disclosed compositions are also provided. Thecompositions of the present disclosure generally include apharmacologically active agent, a high viscosity liquid carrier material(HVLCM) and a solvent. In some embodiments, the compositions alsoinclude one or more of a rheology modifier, a network former, ahydrophilic agent, a viscosity enhancing agent and a stabilizing agent.

In some embodiments, the inclusion of a viscosity enhancing agent, e.g.,a mineral particle such as silicon dioxide, within a specifiedconcentration range in the composition surprisingly provides fordecreased variability in the dissolution profile of the active agentfrom the composition, e.g., as evidenced by a relative decrease ininter-capsule dissolution profile variability, while maintaining anacceptable level of rigidity/or viscosity which does not significantlyinterfere with the processability of the composition. This unexpected,beneficial balance between dissolution variability and processabilitymay be achieved by including the viscosity enhancing agent, e.g., amineral particle such as silicon dioxide, at from about 2.4 to about 5.4percent by weight relative to the total weight of the composition.

As demonstrated by the present disclosure, the concentration of arheology modifier, such as isopropyl myristate (IPM), in apharmaceutical composition may also have a significant effect on samplevariability, e.g., as evidenced by inter-capsule dissolution profilevariability. It is an unexpected discovery of the present disclosurethat providing a relatively low concentration range of a rheologymodifier such as IPM, e.g., at from about 2% to about 10% by weightbased on the total weight of the composition, contributes to a desirablepharmacokinetic profile while reducing inter-capsule dissolution profilevariability.

The present disclosure also provides improved compositions which exhibita reduction in a storage-time dependent change in mean in vitro releaseof the active agent from the composition. Without intending to be boundby any particular theory, it is believed that reducing the amount ofwater available to the compositions of the present disclosure mayminimize these effects. For example, by utilizing HPMC capsules (˜2-6%w/w water, e.g., ˜4-6% w/w water) instead of gelatin capsules (˜13-16%w/w water) the amount of water available to the compositions may bereduced. Accordingly, in some embodiments, the compositions of thepresent disclosure are specifically encapsulated within capsules havinglower water content than gelatin capsules. Thus, in some embodiments acomposition according to the present disclosure is one which hasrelatively low water content. For example, in some embodiments, acomposition according to the present disclosure does not include morethan about 5% water by weight, based on total weight of the composition.

In addition, the present disclosure demonstrates that a specified ratiorange of the amount of an HVLCM such as sucrose acetate isobutyrate(SAIB), to a solvent such as triacetin, to a rheology modifier such asIPM in a composition contributes to an improved level of samplevariability, e.g., as evidenced by a reduced time-dependent change in anin vitro release profile of a composition. Accordingly, in someembodiments the compositions of the present disclosure specificallyinclude an HVLCM, a solvent, and a rheology modifier, wherein the HVLCM,the solvent and the rheology modifier are present in the composition ata ratio of about 1.3:1.0:0.3 to about 1.0:1.0:0.05.

Pharmacologically Active Agent

The pharmacologically active agents that may be included in thecompositions of the present disclosure may include any type ofbiologically active compound or composition of matter which, whenadministered to an organism (human or animal subject) induces a desiredpharmacologic and/or physiologic effect by local and/or systemic action.

Examples of such biologically active compounds or compositions of matteruseful in the disclosed compositions include, but are not limited to,opioids, CNS depressants and stimulants.

Opioids are a class of potent narcotics that includes, for example,morphine, codeine, oxycodone and fentanyl and related drugs. Morphine isoften used to alleviate severe pain. Codeine is used for milder pain.Other examples of opioids that can be prescribed to alleviate paininclude oxycodone (e.g. OxyContin®-an oral, controlled release form ofthe drug); propoxyphene (e.g. Darvon™); hydrocodone (e.g. Vicodin™);hydromorphone (e.g. Dilaudid™); and meperidine (e.g. Demerol™)

In addition to relieving pain, opioids can also produce a sensation ofeuphoria, and when taken in large doses, can cause severe respiratorydepression which can be fatal.

CNS depressants slow down normal brain function by increasing GABAactivity, thereby producing a drowsy or calming effect. In higher doses,some CNS depressants can become general anesthetics, and in very highdoses may cause respiratory failure and death. CNS depressants arefrequently abused, and often the abuse of CNS depressants occurs inconjunction with the abuse of another substance or drug, such as alcoholor cocaine. Many deaths occur yearly through such drug abuse. CNSdepressants can be divided into two groups, based on their chemistry andpharmacology: (1) Barbiturates, such as mephobarbital (e.g. Mebaral™)and pentobarbital sodium (e.g. Nembutal™), which are used to treatanxiety, tension, and sleep disorders. (2) Benzodiazepines, such asdiazepam (e.g. Valium™), chlordiazepoxide HCl (e.g. Librium™), andalprazolam (e.g. Xanax™), which can be prescribed to treat anxiety,acute stress reactions, and panic attacks. Benzodiazepines that have amore sedating effect, such as triazolam (e.g. Halcion™) and estazolam(e.g. ProSom™) can be prescribed for short-term treatment of sleepdisorders.

Stimulants are a class of drugs that enhance brain activity—they causean increase in alertness, attention, and energy that is accompanied byincreases in blood pressure, heart rate, and respiration. Stimulants arefrequently prescribed for treating narcolepsy, attention-deficithyperactivity disorder (ADHD), and depression. Stimulants may also beused for short-term treatment of obesity, and for patients with asthma.Stimulants such as dextroamphetamine (Dexedrine™) and methylphenidate(Ritalin™) have chemical structures that are similar to key brainneurotransmitters called monoamines, which include norepinephrine anddopamine. Stimulants increase the levels of these chemicals in the brainand body. This, in turn, increases blood pressure and heart rate,constricts blood vessels, increases blood glucose, and opens up thepathways of the respiratory system. In addition, the increase indopamine is associated with a sense of euphoria that can accompany theuse of these drugs.

Taking high doses of a stimulant can result in an irregular heartbeat,dangerously high body temperatures, and/or the potential forcardiovascular failure or lethal seizures. Taking high doses of somestimulants repeatedly over a short period of time can lead to hostilityor feelings of paranoia in some individuals.

One class of biologically active compounds that may be included in thecompositions of the present disclosure is the opioids class, whichincludes alfentanil, allylprodine, alphaprodine, anileridine,apomorphine, apocodeine, benzylmorphine, bezitramide, buprenorphine,butorphanol, clonitazene, codeine, cyclazocine, cyclorphen,cyprenorphine, desomorphine, dextromoramide, dextromethorphan, dezocine,diampromide, dihydrocodeine, dihydromorphine, dimenoxadol,dimepheptanol, dimethylthiambutene, dioxyaphetyl butyrate, dipipanone,eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine,etonitazene, fentanyl, heroin, hydrocodone, hydroxymethylmorphinan,hydromorphone, hydroxypethidine, isomethadone, ketobemidone,levallorphan, levorphanol, levophenacylmorphan, levomethorphan,lofentanil, meperidine, meptazinol, metazocine, methadone,methylmorphine, metopon, morphine, myrophine, nalbuphine, narceine,nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine,norpipanone, ohmefentanyl, opium, oxycodone, oxymorphone, papaveretum,pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine,pholcodine, piminodine, piritramide, propheptazine, promedol, profadol,properidine, propiram, propoxyphene, remifentanyl, sufentanyl, tramadol,tilidine, naltrexone, naloxone, nalmefene, methylnaltrexone, naloxonemethiodide, nalorphine, naloxonazine, nalide, nalmexone, nalbuphine,nalorphine dinicotinate, naltrindole (NTI), naltrindole isothiocyanate(NTII), naltriben (NTB), nor-binaltorphimine (nor-BNI), tapentadol,beta-funaltrexamine (b-FNA), 7-Benzylidenenaltrexone (BNTX), cyprodime,N,N-diallyl-Tyr-Aib-Aib-Phe-Leu (ICI-174,864),3-[1-(3-hydroxy-3-phenylpropyl)-3,4-dimethylpiperidin-4-yl]phenol(LY117413),[(−)-(1R,5R,9R)-5,9-diethyl-2-(3-furylmethyl)-2′-hydroxy-6,7-benzomorphan](MR2266), etorphine, [D-Ala², NMe-Phe⁴, Gly-ol⁵]-enkephalin (DAMGO),CTOP (CAS No:103429-31-8), diprenorphine, naloxone benzoylhydrazone,bremazocine, ethylketocyclazocine, (U50,488), (U69,593), spiradoline,[D-Pen^(2,5)]Enkephalin (DPDPE), [D-Ala2,Glu4] deltorphin, [D-Ser²,Leu⁵, Thr⁶]-enkephalin (DSLET), Met-enkephalin, Leu-enkephalin,β-endorphin, dynorphin A, dynorphin B, a-neoendorphin, or an opioidhaving the same pentacyclic nucleus as nalmefene, naltrexone,buprenorphine, levorphanol, meptazinol, pentazocine, dezocine, or theirpharmacologically effective esters or salts.

In some embodiments, opioids for use in the compositions of the presentdisclosure are selected from morphine, hydrocodone, oxycodone, codeine,fentanyl (and its relatives), hydromorphone, meperidine, methadone,oxymorphone, propoxyphene or tramadol, or mixtures thereof. In someembodiments, opioids for use in the compositions of the presentdisclosure are selected from oxycodone, oxymorphone, hydrocodone andhydromorphone. In some embodiments, the opioids for use in thecompositions of the present disclosure may be micronized. With respectto the opioid oxycodone, it may be beneficial to provide compositionsthat have a reduced level of peroxide degradation products such as alphabeta unsaturated ketones (ABUK). In such cases, the compositions of thepresent disclosure can be subjected to peroxide contaminant reductionand/or removal techniques in accordance with known methods.

Other pharmacologically active compounds or compositions of matteruseful in the disclosed compositions include prochlorperazine edisylate,ferrous sulfate, aminocaproic acid, potassium chloride, mecamylamine,procainamide, amphetamine (all forms including dexamphetamine,dextroamphetamine, d-S-amphetamine, and levoamphetamine), benzphetamine,isoproternol, methamphetamine, dexmethamphetamine, phenmetrazine,bethanechol, metacholine, pilocarpine, atropine, methascopolamine,isopropamide, tridihexethyl, phenformin, methylphenidate (all formsincluding dexmethylphenidate, d-threo methylphenidate, and dl-threomethylphenidate), oxprenolol, metroprolol, cimetidine, diphenidol,meclizine, prochlorperazine, phenoxybenzamine, thiethylperazine,anisindone, diphenadione erythrityl, digoxin, isofurophate, reserpine,acetazolamide, methazolamide, bendroflumethiazide, chlorpropamide,tolazamide, chlormadinone, phenaglycodol, allopurinol, aluminum aspirin,methotrexate, acetyl sulfisoxazole, erythromycin, progestins, estrogenicprogrestational, corticosteroids, hydrocortisone, hydrocorticosteroneacetate, cortisone acetate, triamcinolone, methyltesterone, 17beta-estradiol, ethinyl estradiol, ethinyl estradiol 3-methyl ether,prednisolone, 17-hydroxyprogesterone acetate, 19-nor-progesterone,norgestrel, orethindone, norethiderone, progesterone, norgestrone,norethynodrel, aspirin, indomethacin, naproxen, fenoprofen, sulindac,diclofenac, indoprofen, nitroglycerin, propranolol, metroprolol, sodiumvalproate, valproic acid, taxanes such as paclitaxel, camptothecins suchas 9-aminocamptothecin, oxprenolol, timolol, atenolol, alprenolol,cimetidine, clonidine, imipramine, levodopa, chloropropmazine,resperine, methyldopa, dihydroxyphenylalanine, pivaloyloxyethyl ester ofα-methyldopa hydrochloride, theophylline, calcium gluconate ferrouslactate, ketoprofen, ibuprofen, cephalexin, haloperiodol, zomepirac,vincamine, diazepam, phenoxybenzamine, β-blocking agents,calcium-channel blocking drugs such as nifedipine, diltiazen, verapamil,lisinopril, captopril, ramipril, fosimopril, benazepril, libenzapril,cilazapril cilazaprilat, perindopril, zofenopril, enalapril, indalapril,qumapril, and the like.

The active agent can be present in the compositions of the presentdisclosure in a neutral form, as a free base form, or in the form of apharmaceutically acceptable salt. Pharmaceutically acceptable saltsinclude salts of acidic or basic groups, which groups may be present inthe active agents. Those active agents that are basic in nature arecapable of forming a wide variety of salts with various inorganic andorganic acids. Pharmaceutically acceptable acid addition salts of basicactive agents suitable for use herein are those that form acid additionsalts, i.e., salts including pharmacologically acceptable anions, suchas the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate,bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate,salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate,succinate, maleate, gentisinate, fumarate, gluconate, glucaronate,saccharate, formate, benzoate, glutamate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Active agents thatinclude an amino moiety may form pharmaceutically acceptable salts withvarious amino acids, in addition to the acids mentioned above. Suitablebase salts can be formed from bases which form non-toxic salts, forexample, aluminium, calcium, lithium, magnesium, potassium, sodium, zincand diethanolamine salts. See, e.g., Berge et al. (1977) J. Pharm. Sci.66:1-19, the disclosure of which is incorporated by reference herein.

In the compositions of the present disclosure, the pharmacologicallyactive agent will be dissolved (fully or partially) in one or morecomponents of the composition or dispersed within one or more componentsof the composition. The phrase “dissolved or dispersed” is intended toencompass all means of establishing a presence of the active agent inthe subject compositions and includes dissolution, dispersion, partialdissolution and dispersion, and/or suspension and the like. In addition,in certain embodiments of the present disclosure wherein the activeagent is in a solid particulate form suspended within one or more othercomponents of the composition, the active agent particulate may bepre-treated with a micronization process such as those described in U.S.Application Publication No. 2009/0215808, the disclosure of which isincorporated by reference herein, to provide a particle populationhaving a substantially homogeneous particle size the bulk of which fallwithin the micron (μm) range.

The pharmacologically active agent, which can include one or moresuitable active agent, may be present in the disclosed compositions inan amount of from about 50 to about 0.1 percent by weight relative tothe total weight of the composition (wt %), e.g., in an amount of fromabout 40 to about 0.1 wt %, in an amount of from about 30 to about 0.1wt %, in an amount of from about 20 to about 0.1 wt %, in an amount offrom about 10 to about 0.1 wt %, in an amount of from about 9 to about0.1 wt %, in an amount of from about 8 to about 0.1 wt %, in an amountof from about 7 to about 0.1 wt %, in an amount of from about 6 to about0.1 wt %, in an amount of from about 5 to about 0.1 wt %, in an amountof from about 4 to about 0.1 wt %, in an amount of from about 3 to about0.1 wt %, in an amount of from about 2 to about 0.1 wt %, or in anamount of from about 1 to about 0.1 wt %, depending upon the identity ofthe active agent, the desired dose required for the dosage form, and theintended use thereof.

In some embodiments, the pharmacologically active agent may be presentin the disclosed compositions in an amount from about 0.1 to about 5 w%, in an amount from about 5 to about 10 w %, in an amount from about 10to about 20 w %, in an amount from about 20 to about 30 w %, in anamount from about 30 to about 40 w %, or in an amount from about 40 toabout 50 w %, depending upon the identity of the active agent, thedesired dose required for the dosage form, and the intended use thereof.

In some embodiments, the active agent is present in the composition inan amount of about 1 to about 10 wt %, and can thus be loaded into asuitable dosage form to provide single dosages ranging from about 0.01mg to about 1000 mg, or from about 0.1 mg to about 500 mg, or from about2 mg to about 250 mg, or from about 2 mg to about 250 mg, or from about2 mg to about 150 mg, or from about 5 mg to about 100 mg, or from about5 mg to about 80 mg. For example, in some embodiments, the active agentis present in the composition in an amount of from about 2 wt % to about9 wt %, from about 3 wt % to about 8 wt %, from about 4 wt % to about 7wt %, or from about 5 wt % to about 6 wt %. In some embodiments, theactive agent is present in the composition in an amount of about 1 wt %,about 2 wt %, about 3 wt %, about 4 wt %, about 5 wt %, about 6 wt %,about 7 wt %, about 8 wt %, about 9 wt %, or about 10 wt %.

For some embodiments that include an opioid active agent, exemplarysingle dosages include, but are not limited to, about 1, about 2, about3, about 4, about 5, about 10, about 15, about 20, about 25, about 30,about 35, about 40, about 45, about 50, about 55, about 60, about 65,about 70, about 75, about 80, about 85, about 90, about 95, about 100,about 110, about 120, about 130, about 140, about 150 and about 160 mg.

In other embodiments that include a CNS depressant or CNS stimulant,exemplary single dosages include, but are not limited to, about 5, about6, about 7, about 8, about 9, about 10, about 11, about 12, about 13,about 14, about 15, about 16, about 17, about 18, about 19, about 20,about 21, about 22, about 23, about 24, about 25, about 26, about 27,about 28, about 29, about 30, about 31, about 32, about 33, about 34,about 35, about 36, about 37, about 38, about 39, about 40, about 41,about 42, about 43, about 44, about 45, about 46, about 47, about 48,about 49, about 50, about 51, about 52, about 53, about 54, about 55,about 56, about 57, about 58, about 59, about 60, about 61, about 62,about 63, about 64, about 65, about 66, about 67, about 68, about 69,about 70, about 71, about 72, about 73, about 74, about 75, about 76,about 77, about 78, about 79, about 80, about 81, about 82, about 83,about 84, about 85, about 86, about 87, about 88, about 89, about 90,about 91, about 92, about 93, about 94, about 95, about 96, about 97,about 98, about 99, and about 100 mg.

In some embodiments, where the active agent includes oxycodone freebase, the active agent is present in the composition in an amount offrom about 50 to about 0.1 percent by weight relative to the totalweight of the composition (wt %), e.g., in an amount of from about 40 toabout 0.1 wt %, in an amount of from about 30 to about 0.1 wt %, in anamount of from about 20 to about 0.1 wt %, in an amount of from about 10to about 0.1 wt %, in an amount of from about 9 to about 0.1 wt %, in anamount of from about 8 to about 0.1 wt %, in an amount of from about 7to about 0.1 wt %, in an amount of from about 6 to about 0.1 wt %, in anamount of from about 5 to about 0.1 wt %, in an amount of from about 4to about 0.1 wt %, in an amount of from about 3 to about 0.1 wt %, in anamount of from about 2 to about 0.1 wt %, or in an amount of from about1 to about 0.1 wt %.

In some embodiments, where the active agent includes oxycodone freebase, the active agent may be present in the disclosed compositions inan amount from about 0.1 to about 5 w %, in an amount from about 5 toabout 10 w %, in an amount from about 10 to about 20 w %, in an amountfrom about 20 to about 30 w %, in an amount from about 30 to about 40 w%, or in an amount from about 40 to about 50 w %.

In some embodiments, where the active agent comprises oxycodone freebase, the active agent is present in the composition in an amount ofabout 1 to about 10 wt %, and can thus be loaded into a suitable dosageform to provide single dosages ranging from about 0.01 mg to about 1000mg, or from about 0.1 mg to about 500 mg, or from about 2 mg to about250 mg, or from about 2 mg to about 250 mg, or from about 2 mg to about150 mg, or from about 5 mg to about 100 mg, or from about 5 mg to about80 mg. For example, in some embodiments, where the active agentcomprises oxycodone free base, the active agent is present in thecomposition in an amount of from about 2 wt % to about 9 wt %, fromabout 3 wt % to about 8 wt %, from about 4 wt % to about 7 wt %, or fromabout 5 wt % to about 6 wt %. In some embodiments, where the activeagent comprises oxycodone free base, the active agent is present in thecomposition in an amount of about 1 wt %, about 2 wt %, about 3 wt %,about 4 wt %, about 5 wt %, about 6 wt %, about 7 wt %, about 8 wt %,about 9 wt %, or about 10 wt %.

For some embodiments, where the active agent comprises oxycodone freebase, exemplary single dosages include, but are not limited to, about 1,about 2, about 3, about 4, about 5, about 10, about 15, about 20, about25, about 30, about 35, about 40, about 45, about 50, about 55, about60, about 65, about 70, about 75, about 80, about 85, about 90, about95, about 100, about 110, about 120, about 130, about 140, about 150,and about 160 mg.

In some embodiments, where the active agent is oxycodone free base, theactive agent is present in the composition in an amount of about 1 toabout 10 wt %, and can thus be loaded into a suitable dosage form toprovide single dosages ranging from about 0.01 mg to 1000 mg, or fromabout 0.1 mg to 500 mg, or from about 2 mg to 250 mg, or from about 2 mgto 250 mg, or from about 2 mg to 150 mg, or from about 5 mg to 100 mg,or from about 5 mg to 80 mg. For example, in some embodiments, theoxycodone free base is present in the composition in an amount of fromabout 2 wt % to about 9 wt %, from about 3 wt % to about 8 wt %, fromabout 4 wt % to about 7 wt %, or from about 5 wt % to about 6 wt %.

In some embodiments, the oxycodone free base is present in thecomposition in an amount of about 1 wt %, about 2 wt %, about 3 wt %,about 4 wt %, about 5 wt %, about 6 wt %, about 7 wt %, about 8 wt %,about 9 wt %, or about 10 wt %.

The precise amount of active agent desired can be determined by routinemethods well known to pharmacological arts, and will depend on the typeof agent, and the pharmacokinetics and pharmacodynamics of that agent.

High Viscosity Liquid Carrier Material (HVLCM)

An HVLCM is a non-polymeric, non-water soluble liquid material having aviscosity of at least 5000 cP at 37° C. that does not crystallize neatat 25° C. and 1 atmosphere. The term “non-water soluble” refers to amaterial that is soluble in water to a degree of less than one percentby weight at 25° C. and 1 atmosphere. The term “non-polymeric” refers toesters or mixed esters having essentially no repeating units in the acidmoiety of the ester, as well as esters or mixed esters having acidmoieties wherein functional units in the acid moiety are repeated asmall number of times (i.e., oligomers). Generally, materials havingmore than five identical and adjacent repeating units or mers in theacid moiety of the ester are excluded by the term “non-polymeric” asused herein, but materials containing dimers, trimers, tetramers, orpentamers are included within the scope of this term. When the ester isformed from hydroxy-containing carboxylic acid moieties that can furtheresterify, such as lactic acid or glycolic acid, the number of repeatunits is calculated based upon the number of lactide or glycolidemoieties, rather than upon the number of lactic acid or glycolic acidmoieties, where a lactide repeat unit contains two lactic acid moietiesesterified by their respective hydroxy and carboxy moieties, and where aglycolide repeat unit contains two glycolic acid moieties esterified bytheir respective hydroxy and carboxy moieties. Esters having 1 to about20 etherified polyols in the alcohol moiety thereof, or 1 to about 10glycerol moieties in the alcohol moiety thereof, are considerednon-polymeric as that term is used herein. HVLCMs may becarbohydrate-based, and may include one or more cyclic carbohydrateschemically combined with one or more carboxylic acids. HVLCMs alsoinclude non-polymeric esters or mixed esters of one or more carboxylicacids, having a viscosity of at least 5,000 cP at 37° C., that do notcrystallize neat at 25° C. and 1 atmosphere, wherein when the estercontains an alcohol moiety (e.g., glycerol). The ester may, for exampleinclude from about 2 to about 20 hydroxy acid moieties. Various HVLCMs,which may be used be included in disclosed compositions are described inU.S. Pat. Nos. 5,747,058; 5,968,542; and 6,413,536; the disclosures ofeach of which are incorporated by reference herein. The presentlydisclosed compositions may employ any HVLCM described in these patentsbut is not limited to any specifically described materials.

The HVLCM may be present in the composition at from about 35% by weightto about 45% by weight, based on total weight of the composition. Forexample, the HVLCM may be present in the composition at from about 36%by weight to about 45% by weight, from about 37% by weight to about 45%by weight, from about 38% by weight to about 45% by weight, from about39% by weight to about 45% by weight, from about 40% by weight to about45% by weight, from about 41% by weight to about 45% by weight, fromabout 42% by weight to about 45% by weight, from about 43% by weight toabout 45% by weight, or from about 44% by weight to about 45% by weightrelative to the total weight of the composition. In some embodiments,the HVLCM may be present in the composition at from about 35% by weightto about 37% by weight, from about 37% by weight to about 39% by weight,from about 39% by weight to about 41% by weight, from about 41% byweight to about 43% by weight, or from about 43% by weight to about 45%by weight relative to the total weight of the composition. In someembodiments, the HVLCM may be present in the composition at about 35% byweight, about 36% by weight, about 37% by weight, about 38% by weight,about 39% by weight, about 40% by weight, about 41% by weight, about 42%by weight, about 43% by weight, about 44% by weight, or about 45% byweight relative to the total weight of the composition.

In some embodiments, the amount of the HVLCM present in the compositionis provided relative to the amount of the solvent present in thecomposition. For example, the HVLCM and the solvent may be provided inthe composition at a ratio of about 1.3:1 to about 1:1, e.g., about1.20:1 to about 1:1, about 1.15:1 to about 1:1, about 1.10:1 to about1:1, or about 1:1. For example, in some embodiments, the HVLCM and thesolvent may be provided in the composition at a ratio of about 1.30:1.0,about 1.25:1.0, about 1.20:1.0, about 1.15:1.0, or about 1.0:1.0. Insome embodiments, the HVLCM and the solvent may be provided in thecomposition at a ratio of about 0.6:1 to about 1.6:1, e.g., about 0.8:1to about 1.5:1, or about 0.9:1 to about 1.5:1. For example, in someembodiments, the HVLCM and the solvent (e.g., triacetin) may be providedin the composition at a ratio of about 0.6:1.0, about 0.7:1.0, about0.8:1.0, about 0.9:1.0, about 1.0:1.0, about 1.1:1.0, about 1.2:1.0,about 1.3:1.0, about 1.4:1.0, about 1.5:1.0, or about 1.6:1.0.

In some embodiments, Sucrose Acetate Isobutyrate (“SAIB”) may beincluded in the composition as the HVLCM or the HVLCM may include SAIB.SAIB is a non-polymeric highly viscous liquid at temperatures rangingfrom −80° C. to over 100° C., it is a fully esterified sucrosederivative, at a nominal ratio of six isobutyrates to two acetates. Thechemical structure of SAIB is provided in U.S. Application PublicationNo. 2009/0215808, the disclosure of which is incorporated by referenceherein. The SAIB material is available from a variety of commercialsources including Eastman Chemical Company, where it is available as amixed ester that does not crystallize but exists as a very highlyviscous liquid. It is a hydrophobic, non-crystalline, low molecularweight molecule that is water insoluble and has a viscosity that varieswith temperature. For example, pure SAIB exhibits a viscosity ofapproximately 2,000,000 centipoise (cP) at ambient temperature (RT) andapproximately 600 cP at 80° C. The SAIB material has uniquesolution-viscosity relationship in that a SAIB solution established in anumber of organic solvents has a significantly lower viscosity valuethan the pure SAIB material, and therefore the SAIB-organic solventsolutions render themselves capable of processing using conventionalequipment such as mixers, liquid pumps and capsule production machines.SAIB also has applications in drug formulation and delivery, for exampleas described in U.S. Pat. Nos. 5,747,058; 5,968,542; 6,413,536; and6,498,153, the disclosure of which are incorporated by reference herein.

In the compositions of the present disclosure, SAIB may be used as theHVLCM or the HVLCM may include SAIB at from about 35% by weight to about45% by weight, based on total weight of the composition. For example,the SAIB may be present in the composition at from about 36% by weightto about 45% by weight, from about 37% by weight to about 45% by weight,from about 38% by weight to about 45% by weight, from about 39% byweight to about 45% by weight, from about 40% by weight to about 45% byweight, from about 41% by weight to about 45% by weight, from about 42%by weight to about 45% by weight, from about 43% by weight to about 45%by weight, or from about 44% by weight to about 45% by weight relativeto the total weight of the composition. In some embodiments, the SAIBmay be present in the composition at from about 35% by weight to about37% by weight, from about 37% by weight to about 39% by weight, fromabout 39% by weight to about 41% by weight, from about 41% by weight toabout 43% by weight, or from about 43% by weight to about 45% by weightrelative to the total weight of the composition. In some embodiments,the SAIB may be present in the composition at about 35% by weight, about36% by weight, about 37% by weight, about 38% by weight, about 39% byweight, about 40% by weight, about 41% by weight, about 42% by weight,about 43% by weight, about 44% by weight, or about 45% by weightrelative to the total weight of the composition.

In some embodiments, the amount of SAIB present in the composition isprovided relative to the amount of the solvent (e.g., triacetin) presentin the composition. For example, the SAIB and the solvent may beprovided in the composition at a ratio of about 1.3:1 to about 1:1,e.g., about 1.20:1 to about 1:1, about 1.15:1 to about 1:1, about 1.10:1to about 1:1, or about 1:1. For example, in some embodiments, the SAIBand the solvent may be provided in the composition at a ratio of about1.30:1.0, about 1.25:1.0, about 1.20:1.0, about 1.15:1.0, or about1.0:1.0. In some embodiments, the SAIB and the solvent may be providedin the composition at a ratio of about 0.6:1 to about 1.6:1, e.g., about0.8:1 to about 1.5:1, or about 0.9:1 to about 1.5:1. For example, insome embodiments, the SAIB and the solvent (e.g., triacetin) may beprovided in the composition at a ratio of about 0.6:1.0, about 0.7:1.0,about 0.8:1.0, about 0.9:1.0, about 1.0:1.0, about 1.1:1.0, about1.2:1.0, about 1.3:1.0, about 1.4:1.0, about 1.5:1.0, or about 1.6:1.0.

In some embodiments, it may be beneficial to provide a SAIB carriermaterial having a lower peroxide level to avoid peroxide-baseddegradation of various components of the composition and/or activeagent. See, e.g., U.S. Patent Application Publication Number US2007/0027105, “Peroxide Removal From Drug Delivery Vehicle”, thedisclosure of which is incorporated by reference herein.

Solvents

Solvents may be used in the compositions of the present disclosure todissolve one or more of the following constituents: HVCLMs; activeagents; network formers; rheology modifiers; viscosity enhancing agents;hydrophilic agents; and stabilizing agents. In some embodiments, thesolvent can dissolve both the HVLCM and the network former. In someembodiments of the compositions of the present disclosure, a compositionmay include both a hydrophilic solvent and a hydrophobic solvent.Organic solvents suitable for use with the compositions of the presentdisclosure include, but are not limited to: substituted heterocycliccompounds such as N-methyl-2-pyrrolidone (NMP) and 2-pyrrolidone(2-pyrol); triacetin; esters of carbonic acid and alkyl alcohols such aspropylene carbonate, ethylene carbonate and dimethyl carbonate; fattyacids such as acetic acid, lactic acid and heptanoic acid; alkyl estersof mono-, di-, and tricarboxylic acids such as 2-ethyoxyethyl acetate,ethyl acetate, methyl acetate, ethyl lactate, ethyl butyrate, diethylmalonate, diethyl glutonate, tributyl citrate, diethyl succinate,tributyrin, dimethyl adipate, dimethyl succinate, dimethyl oxalate,dimethyl citrate, triethyl citrate, acetyl tributyl citrate, glyceryltriacetate; alkyl ketones such as acetone and methyl ethyl ketone; etheralcohols such as 2-ethoxyethanol, ethylene glycol dimethyl ether,glycofurol and glycerol formal; alcohols such as benzyl alcohol, ethanoland propanol; polyhydroxy alcohols such as propylene glycol,polyethylene glycol (PEG), glycerin (glycerol), 1,3-butyleneglycol, andisopropylidene glycol (2,2-dimethyl-1,3-dioxolone-4-methanol); Solketal;dialkylamides such as dimethylformamide, dimethylacetamide;dimethylsulfoxide (DMSO) and dimethylsulfone; tetrahydrofuran; lactonessuch as ε-caprolactone and butyrolactone; cyclic alkyl amides such ascaprolactam; aromatic amides such as N,N-dimethyl-m-toluamide, and1-dodecylazacycloheptan-2-one; and the like; and mixtures andcombinations thereof.

In some embodiments, the solvent includes or is selected from triacetin,N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethylsulfoxide, ethyl lactate,propylene carbonate, and glycofurol. In some embodiments, the solvent istriacetin which is a hydrophilic solvent. In some embodiments, thehydrophilic triacetin solvent can be combined with a hydrophobic solventto provide a hydrophobic/hydrophilic solvent system within thecomposition.

The solvent, which can include one or more suitable solvent materials,can be present in the compositions at from about 31% by weight to about45% by weight, based on total weight of the composition. For example,the solvent may be present in the composition at from about 32% byweight to about 45% by weight, at from about 33% by weight to about 45%by weight, at from about 34% by weight to about 45% by weight, at fromabout 35% by weight to about 45% by weight, at from about 36% by weightto about 45% by weight, at from about 37% by weight to about 45% byweight, at from about 38% by weight to about 45% by weight, at fromabout 39% by weight to about 45% by weight, at from about 40% by weightto about 45% by weight, at from about 41% by weight to about 45% byweight, at from about 42% by weight to about 45% by weight, at fromabout 43% by weight to about 45% by weight, or at from about 44% byweight to about 45% by weight relative to the total weight of thecomposition. In some embodiments, the solvent may be present in thecomposition at from about 31% by weight to about 33% by weight, at fromabout 33% by weight to about 35% by weight, at from about 35% by weightto about 37% by weight, at from about 37% by weight to about 39% byweight, at from about 39% by weight to about 41% by weight, at fromabout 41% by weight to about 43% by weight, or at from about 43% byweight to about 45% by weight relative to the total weight of thecomposition. In some embodiments, the solvent may be present in thecomposition at about 31% by weight, about 32% by weight, about 33% byweight, about 34% by weight about 35% by weight, about 36% by weight,about 37% by weight, about 38% by weight, about 39% by weight, about 40%by weight, about 41% by weight, about 42% by weight, about 43% byweight, about 44% by weight, or about 45% by weight relative to thetotal weight of the composition.

Rheology Modifier

Rheology refers to the property of deformation and/or flow of a liquid,and rheology modifiers are used to modify viscosity and flow of a liquidcomposition. Rheology modifiers, which may be used in the compositionsof the present disclosure include, for example, caprylic/caprictriglyceride (e.g., Miglyol® 810 or Miglyol® 812), isopropyl myristate(IM or IPM), ethyl oleate, triethyl citrate, dimethyl phthalate, andbenzyl benzoate.

In some embodiments, the rheology modifier is or includes IPM. Therheology modifier, which can include one or more suitable rheologymodifier materials, can be present in the compositions at from about 2to about 10 percent by weight relative to the total weight of thecomposition (wt %), e.g., at from about 2 to about 8 wt %, at from about2 to about 6 wt %, or at from about 2 to about 4 wt %. In someembodiments, the rheology modifier is preset in the compositions at fromabout 2 to about 4 wt %, at from about 4 to about 6 wt %, at from about6 to about 8 wt %, or at from about 8 to about 10 wt %. For example, insome embodiments, the rheology modifier, e.g., IPM, is present in thecomposition at about 2 wt %, about 3 wt %, about 4 wt %, about 5 wt %,about 6 wt %, about 7 wt %, about 8 wt %, about 9 wt %, or about 10 wt%.

In some embodiments, the rheology modifier is present in thecompositions of the present disclosure in an amount relative to theamount of solvent in the compositions. For example, in some embodimentsthe solvent and the rheology modifier are present in the compositions ata ratio of about 1:0.3 to about 1.0:0.05, e.g., about 1:0.2 to about1:0.06, about 1:0.1 to about 1:0.07, or about 1:0.09 to about 1:0.08.For example, in some embodiments, the solvent and the rheology modifierare present in the compositions at a ratio of about 1.0:0.3, about1.0:0.2, about 1.0:0.1, about 1.0:0.09, about 1.0:0.08, about 1.0:0.07,about 1.0:0.06, or about 1.0:0.05. In some embodiments, where thesolvent is triacetin and the rheology modifier is IPM, the solvent andthe rheology modifier are present in the compositions at a ratio ofabout 1.0:0.3, about 1.0:0.2, about 1.0:0.1, about 1.0:0.09, about1.0:0.08, about 1.0:0.07, about 1.0:0.06, or about 1.0:0.05.

Network Former

Network formers may be added to a composition such that, upon exposureto an aqueous environment, they form a three dimensional network withinthe composition. While not intending to be bound by any particulartheory, it is believed that the network former allows the formation of amicro-network within the composition upon exposure to an aqueousenvironment. This micro-network formation appears to be due, at least inpart, to a phase inversion (e.g., a change in glass transitiontemperature, T_(g)) of the network former. The result is believed to bea skin or surface layer of precipitated network former at the interfacebetween the composition and the aqueous environment of the GI tract, aswell as the formation of a three-dimensional micro-network ofprecipitated network former within the composition. The network formeris selected so as to have good solubility in the selected solvent usedin the compositions, for example a solubility of between about 0.1 and20 wt %. Additionally, good network formers will typically have a Log Pbetween about −1 to 7. Suitable network formers include, for example,cellulose acetate butyrate (“CAB”), carbohydrate polymers, organic acidsof carbohydrate polymers and other polymers, hydrogels, celluloseacetate phthalate, ethyl cellulose, Pluronic® (nonionic triblockcopolymer), Eudragit® (polymethacrylate), Carbomer™ (polyacrylic acid),hydroxyl propyl methyl cellulose, other cellulose acetates such ascellulose triacetate, Poly(methyl methacrylate) (PMMA), as well as anyother material capable of associating, aligning or congealing to formthree-dimensional networks in an aqueous environment.

In some embodiments, the network former used in the compositions of thepresent disclosure is or includes a CAB having a number averagemolecular weight ranging from about 50,000 Daltons to about 100,000Daltons, e.g., from about 60,000 Daltons to about 100,000 Daltons, fromabout 70,000 Daltons to about 100,000 Daltons, from about 80,000 Daltonsto about 100,000 Daltons, or from about 90,000 Daltons to about 100,000Daltons. In some embodiments, the network former used in thecompositions of the present disclosure is or includes a CAB having anumber average molecular weight ranging from about 60,000 Daltons toabout 90,000 Daltons, or from about 70,000 Daltons to about 80,000Daltons. In some embodiments, the network former used in thecompositions of the present disclosure is or includes a CAB having anumber average molecular weight of about 50,000 Daltons, about 55,000Daltons, about 60,000 Daltons, about 65,000 Daltons, about 70,000Daltons, about 75,000 Daltons, about 80,000 Daltons, about 85,000Daltons, about 90,000 Daltons, about 95,000 Daltons, or about 100,000Daltons.

In some embodiments, the network former used in the compositions of thepresent disclosure is or includes a CAB having at least one featureselected from a butyryl content ranging from about 17% to about 41%, anacetyl content ranging from about 13% to about 30%, and a hydroxylcontent ranging from about 0.5% to about 1.7%. In some furtherembodiments, the network former used in the compositions of the presentdisclosure is or includes a CAB comprising at least two of a butyrylcontent ranging from about 17% to about 41%, an acetyl content rangingfrom about 13% to about 30%, and a hydroxyl content ranging from about0.5% to about 1.7%. In still further embodiments, the network formerused in the compositions of the present disclosure is or includes a CABcomprising all three of a butyryl content ranging from about 17% toabout 41%, an acetyl content ranging from about 13% to about 30%, and ahydroxyl content ranging from about 0.5% to about 1.7%.

Accordingly, in some embodiments, the network former used in thecompositions of the present disclosure is or includes a CAB having abutyryl content ranging from about 17% to about 41%. In someembodiments, the network former used in the compositions of the presentdisclosure is or includes a CAB having an acetyl content ranging fromabout 13% to about 30%. In some embodiments, the network former used inthe compositions of the present disclosure is or includes a CAB having ahydroxyl content ranging from about 0.5% to about 1.7%. In someembodiments, the network former used in the compositions of the presentdisclosure is or includes a CAB having a butyryl content ranging fromabout 17% to about 41% and an acetyl content ranging from about 13% toabout 30%. In some embodiments, the network former used in thecompositions of the present disclosure is or includes a CAB having abutyryl content ranging from about 17% to about 41% and a hydroxylcontent ranging from about 0.5% to about 1.7%. In some embodiments, thenetwork former used in the compositions of the present disclosure is orincludes a CAB having an acetyl content ranging from about 13% to about30% and a hydroxyl content ranging from about 0.5% to about 1.7%. Instill other embodiments, the network former used in the compositions ofthe present disclosure is or includes a CAB having a butyryl contentranging from about 17% to about 41%, an acetyl content ranging fromabout 13% to about 30%, and a hydroxyl content ranging from about 0.5%to about 1.7%. In further embodiments, in addition to one of the abovefeatures of butyryl content, acetyl content and/or hydroxyl content, theCAB also has a number average molecular weight ranging from about 50,000Daltons to about 100,000 Daltons, e.g., from about 60,000 Daltons toabout 100,000 Daltons, from about 70,000 Daltons to about 100,000Daltons, from about 80,000 Daltons to about 100,000 Daltons, or fromabout 90,000 Daltons to about 100,000 Daltons. In further embodiments,in addition to one of the above features of butyryl content, acetylcontent and/or hydroxyl content, the CAB also has a number averagemolecular weight ranging from about 60,000 Daltons to about 90,000Daltons, or from about 70,000 Daltons to about 80,000 Daltons. Infurther embodiments, in addition to one of the above features of butyrylcontent, acetyl content and/or hydroxyl content, the CAB also has anumber average molecular weight of about 50,000 Daltons, about 55,000Daltons, about 60,000 Daltons, about 65,000 Daltons, about 70,000Daltons, about 75,000 Daltons, about 80,000 Daltons, about 85,000Daltons, about 90,000 Daltons, about 95,000 Daltons, or about 100,000Daltons.

In some embodiments, the network former used in the compositions of thepresent disclosure is or includes cellulose acetate butyrate grade381-20BP (“CAB 381-20BP” available from Eastman Chemicals). In someembodiments, the network former used in the compositions of the presentdisclosure is or includes a CAB, wherein the CAB is a non-biodegradablepolymer material that has the following chemical and physicalcharacteristics: butyryl content of about 36 wt %, acetyl content ofabout 15.5 wt %, hydroxyl content of about 0.8%, a melting point of fromabout 185-196° C., a glass transition temperature of about 128° C., anda number average of from about 66,000 to 83,000, e.g., about 70,000. Insome embodiments, if a CAB material is used in the composition, it maybe subjected to an ethanol washing step (and subsequent drying step)prior to addition to the composition in order to remove potentialcontaminants therefrom.

In some embodiments, the network former of the present disclosurespecifically excludes a network former having an acetyl content of about2.0%, a butyryl content of about 46.0%, a hydroxyl content of 4.8%, amelting point of from about 150-160° C., a glass transition temperatureof about 136° C., and a number average molecular weight of about 20,000,e.g., CAB-553-0.4 available from Eastman Chemicals).

In some embodiments, the network former of the present disclosurespecifically excludes a network former, e.g, a CAB, which is soluble inethanol.

The network former, which can include one or more suitable networkformer materials, can be present in the compositions at from about 0.1to about 20 percent by weight relative to the total weight of thecomposition (wt %), e.g., at from about 1 to about 18 wt %, from about 2to about 10 wt %, from about 4 to about 6 wt %, or at about 5 wt %. Insome embodiments, a network former is present in the compositions of thepresent disclosure at from about 0.1 to about 1 wt %, about 1 to about 5wt %, about 5 to about 10 wt %, about 10 to about 15 wt %, or about 15to about 20 wt %. In some embodiments, a network former is present inthe compositions of the present disclosure at about 0.1 wt %, about 0.5wt %, about 1 wt %, about 2 wt %, about 3 wt %, about 4 wt %, about 5 wt%, about 6 wt %, about 7 wt %, about 8 wt %, about 9 wt %, about 10 wt%, about 11 wt %, about 12 wt %, about 13 wt %, about 14 wt %, about 15wt %, about 16 wt %, about 17 wt %, about 18 wt %, about 19 wt %, orabout 20 wt %.

Hydrophilic Agent

Materials that can be used as “hydrophilic agents” in the compositionsof the present disclosure include those that have natural affinity foraqueous systems. A material may be regarded as a hydrophilic agent forthe purposes of this disclosure if the material displays a watersorption between about 10 to about 100% (w/w). Hydrophilic agents willhave a low Log P value, for example, a Log P of less than +1. Asdiscussed herein above, there are a number of constituents which may beused to produce the compositions of the present disclosure that can beclassed as a hydrophilic material (e.g., a hydrophilic solvent), or atleast a material having a hydrophilic portion (e.g., a rheologymodifier). Since the HVLCM material used in the compositions ishydrophobic, it may be useful to include other materials in thecomposition that are hydrophilic in order to provide a carrier systemthat is balanced to have both hydrophobic and hydrophiliccharacteristics. For example, it is believed that the inclusion of oneor more hydrophilic agents in the compositions of the present disclosuremay participate in the control of active agent diffusion from thecompositions. Accordingly, suitable hydrophilic agents include, but arenot limited to, sugars such as sorbitol, lactose, mannitol, fructose,sucrose and dextrose, salts such as sodium chloride and sodiumcarbonate, starches, hyaluronic acid, glycine, fibrin, collagen,polymers such as hydroxylpropylcellulose (“HPC”),carboxymethylcellulose, hydroxyethyl cellulose (“HEC”); polyethyleneglycol and polyvinylpyrrolidone, and the like. In some embodiments, acontrolled release carrier system is provided that includes HEC as ahydrophilic agent or a component of a hydrophilic agent.

The hydrophilic agent, which can include one or more suitablehydrophilic agent materials, e.g., HEC, can be present in thecompositions at from about 0.1 to about 10 percent by weight relative tothe total weight of the composition (wt %), e.g., from about 1 to about8 wt %, from about 2 to about 7 wt %, from about 3 to about 6 wt %, orfrom about 4 to about 5 wt %. In some embodiments, a hydrophilic agentis present in the compositions of the present disclosure at about 0.1 wt% to about 0.5 wt %, about 0.5 wt % to about 1 wt %, about 1 wt % toabout 5 wt %, or about 5 wt % to about 10 wt %. In some embodiments, ahydrophilic agent is present in the compositions of the presentdisclosure at about 0.1 wt %, about 0.5 wt %, about 1 wt %, about 2 wt%, about 3 wt %, about 4 wt %, about 5 wt %, about 6 wt %, about 7 wt %,about 8 wt %, about 9 wt %, or about 10 wt %.

Viscosity Enhancing Agent

Viscosity enhancing agents can be selected to have good hydrogen bondingcapability, such as a bonding capability greater than or equal to oneper molecule. In certain cases, the viscosity enhancing agent has verylow to no significant solubility in the composition. If the agent issoluble, then, in some embodiments, the solubility is less than 50 wt %.For inorganic or mineral viscosity enhancing agents, it is preferable ifthe material has a specific surface area greater than or equal to about100 m²/g. Suitable viscosity enhancing agents include biodegradable andnon-biodegradable polymer materials. Non-limiting examples of suitablebiodegradable polymers and oligomers include: poly(lactide),poly(lactide-co-glycolide), poly(glycolide), poly(caprolactone),polyamides, polyanhydrides, polyamino acids, polyorthoesters,polycyanoacrylates, poly(phosphazines), poly(phosphoesters),polyesteramides, polydioxanones, polyacetals, polyketals,polycarbonates, polyorthocarbonates, degradable polyurethanes,polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates,polyalkylene succinates, poly(malic acid), chitin, chitosan, andcopolymers, terpolymers, oxidized cellulose, hydroxyethyl cellulose, orcombinations or mixtures of the above materials. Suitablenon-biodegradable polymers include: polyacrylates, ethylene-vinylacetate polymers, cellulose and cellulose derivatives, acyl substitutedcellulose acetates and derivatives thereof including cellulose acetatebutyrate (CAB), which is also used herein as a network former,non-erodible polyurethanes, polystyrenes, polyvinyl chloride, polyvinylfluoride, polyvinyl (imidazole), chlorosulphonated polyolefins,polyethylene oxide, and polyethylene.

Other suitable viscosity enhancing materials include mineral particlessuch as clay compounds, including, talc, bentonite and kaolin; metaloxides including silicon dioxide, zinc oxide, magnesium oxide, titaniumoxide, and calcium oxide; and fumed silica, reagent grade sand,precipitated silica, amorphous silica, colloidal silicon dioxide, fusedsilica, silica gel, and quartz. In some embodiments of the presentdisclosure, a colloidal silicon dioxide, e.g., Cab-O-Sil® M-5P(untreated fumed silica that complies with the pharmacopeia monograph“Colloidal Silicon Dioxide” in the U.S. Pharmacopeia/NationalFormulary), is used in the compositions as a viscosity enhancing agent.

The viscosity enhancing agent, e.g., mineral particle, which can includeone or more suitable viscosity enhancing materials, can be present inthe compositions at from about 2.4 to about 6.0 percent by weightrelative to the total weight of the composition (wt %), e.g., at fromabout 2.5 to about 6.0 wt %, at from about 2.6 to about 6.0 wt %, atfrom about 2.7 to about 6.0 wt %, at from about 2.8 to about 6.0 wt %,at from about 2.9 to about 6.0 wt %, at from about 3.0 to about 6.0 wt%, at from about 3.1 to about 6.0 wt %, at from about 3.2 to about 6.0wt %, at from about 3.3 to about 6.0 wt %, at from about 3.4 to about6.0 wt %, at from about 3.5 to about 6.0 wt %, at from about 3.6 toabout 6.0 wt %, at from about 3.7 to about 6.0 wt %, at from about 3.8to about 6.0 wt %, at from about 3.9 to about 6.0 wt %, at from about4.0 to about 6.0 wt %, at from about 4.1 to about 6.0 wt %, at fromabout 4.2 to about 6.0 wt %, at from about 4.3 to about 6.0 wt %, atfrom about 4.4 to about 6.0 wt %, at from about 4.5 to about 6.0 wt %,at from about 4.6 to about 6.0 wt %, at from about 4.7 to about 6.0 wt%, at from about 4.8 to about 6.0 wt %, at from about 4.9 to about 6.0wt %, at from about 5.0 to about 6.0 wt %, at from about 5.1 to about6.0 wt %, at from about 5.2 to about 6.0 wt %, at from about 5.3 toabout 6.0 wt %, at from about 5.4 to about 6.0 wt %, at from about 5.5to about 6.0 wt %, at from about 5.6 to about 6.0 wt %, at from about5.7 to about 6.0 wt %, at from about 5.8 to about 6.0 wt %, or at fromabout 5.9 to about 6.0 wt %.

In some embodiments, a composition according to the present disclosureincludes a viscosity enhancing agent, e.g., mineral particle, at fromabout 2.4 to about 2.6 wt %, at from about 2.6 wt % to about 2.8 wt %,at from about 2.8 wt % to about 3.0 wt %, at from about 3.0 wt % toabout 3.2 wt %, at from about 3.2 wt % to about 3.4 wt %, at from about3.4 wt % to about 3.6 wt %, at from about 3.6 wt % to about 3.8 wt %, atfrom about 3.8 wt % to about 4.0 wt %, at from about 4.0 wt % to about4.2 wt %, at from about 4.2 wt % to about 4.4 wt %, at from about 4.4 wt% to about 4.6 wt %, at from about 4.6 wt % to about 4.8 wt %, at fromabout 4.8 wt % to about 5.0 wt %, at from about 5.0 wt % to about 5.2 wt%, at from about 5.2 wt % to about 5.4 wt %, at from about 5.4 wt % toabout 5.6 wt %, at from about 5.6 wt % to about 5.8 wt %, or at fromabout 5.8 wt % to about 6.0 wt %.

In some embodiments, a composition according to the present disclosureincludes a viscosity enhancing agent, e.g., mineral particle (e.g.,silicon dioxide) at about 2.4 wt %, about 2.5 wt %, about 2.6 wt %,about 2.7 wt %, about 2.8 wt %, about 2.9 wt %, about 3.0 wt %, about3.1 wt %, about 3.2 wt %, about 3.3 wt %, about 3.4 wt %, about 3.5 wt%, about 3.6 wt %, about 3.7 wt %, about 3.8 wt %, about 3.9 wt %, about4.0 wt %, 4.1 wt %, 4.2 wt %, 4.3 wt %, 4.4 wt %, 4.5 wt %, 4.6 wt %,4.7 wt %, 4.8 wt %, 4.9 wt %, 5.0 wt %, 5.1 wt %, 5.2 wt %, 5.3 wt %,5.4 wt %, 5.5 wt %, 5.6 wt %, 5.7 wt %, 5.8 wt %, 5.9 wt %, or 6.0 wt %.

As discussed in the Examples below, providing a viscosity enhancingagent, e.g., a mineral particle such as silicon dioxide, in an amountoutside of one or more of the ranges specified above may result inundesirable composition characteristics. For example, variability in adissolution profile of the active agent from the composition, e.g., asevidenced by increased inter-capsule variability, may be seen atrelatively low silicon dioxide levels. On the other hand, reducedprocessability may be seen at relatively high silicon dioxide levels dueto an increase in the rigidity and/or viscosity of the composition.Accordingly, in some embodiments, the compositions of the presentdisclosure specifically exclude viscosity enhancing agents, e.g.,mineral particles, in an amount outside of one or more of the rangesspecified above.

In some embodiments an unexpected, beneficial balance betweendissolution variability and processability may be achieved by includingthe viscosity enhancing agent, e.g., mineral particle such as silicondioxide, at from about 2.4 to about 5.4 percent by weight relative tothe total weight of the composition (wt %), e.g., at from about 2.4 toabout 2.6 wt %, at from about 2.6 to about 2.8 wt %, at from about 2.8to about 3.0 wt %, at from about 3.0 to about 3.2 wt %, at from about3.2 to about 3.4 wt %, at from about 3.4 to about 3.6 wt %, at fromabout 3.6 to about 3.8 wt %, at from about 3.8 to about 4.0 wt %, atfrom about 4.0 to about 4.2 wt %, at from about 4.2 to about 4.4 wt %,at from about 4.4 to about 4.6 wt %, at from about 4.6 to about 4.8 wt%, at from about 4.8 to about 5.0 wt %, at from about 5.0 to about 5.2wt %, or at from about 5.2 to about 5.4 wt %. Similarly, a beneficialbalance between dissolution variability and processability may beachieved by including the viscosity enhancing agent, e.g., mineralparticle such as silicon dioxide, at from about 2.6 to about 5.4 wt %,e.g., at from about 2.8 to about 5.4 wt %, at from about 3.0 to about5.4 wt %, at from about 3.2 to about 5.4 wt %, at from about 3.4 toabout 5.4 wt %, at from about 3.6 to about 5.4 wt %, at from about 3.8to about 5.4 wt %, at from about 4.0 to about 5.4 wt %, at from about4.2 to about 5.4 wt %, at from about 4.4 to about 5.4 wt %, at fromabout 4.6 to about 5.4 wt %, at from about 4.8 to about 5.4 wt %, atfrom about 5.0 to about 5.4 wt %, or at from about 5.2 to about 5.4 wt%.

As discussed above, a viscosity enhancing agent, e.g., mineral particle,such as silicon dioxide, when included at specific concentration rangesin the compositions of the present disclosure, may reduce dissolutionvariability of the composition, e.g., inter-capsule dissolutionvariability as determined using a USP Apparatus 2 dissolution tester andmethod as described below in the Examples. See also, USP-NF, Dissolution<711>. Rockville, Md.: US Pharmacopeial Convention; 2008, the disclosureof which is incorporated by reference herein.

Stabilizing Agent

Materials that can be used as stabilizing agents in the compositions ofthe present disclosure include any material or substance that caninhibit or reduce degradation (e.g., by chemical reactions) of othersubstances or substances in the composition with which the stabilizer ismixed. Exemplary stabilizers typically are antioxidants that preventoxidative damage and degradation, e.g., sodium citrate, ascorbylpalmitate, vitamin A, and propyl gallate and/or reducing agents. Otherexamples include ascorbic acid, vitamin E, sodium bisulfite,butylhydroxyl toluene (BHT), BHA, acetylcysteine, monothioglycerol,phenyl-alpha-nathylamine, lecithin, and EDTA. These stabilizingmaterials, which can include one or more of such suitable materials, canbe present in the compositions at from about 0.001 to about 2 percent byweight relative to the total weight of the composition (wt %), e.g., atfrom about 0.01 to about 0.1 wt %, or at from about 0.01 to about 0.02wt %. In some embodiments, the compositions of the present disclosurespecifically exclude a stabilizing agent, such as those listed above.

Surfactants

In some embodiments, a composition according to the present disclosuremay include one or more surfactants. Materials that can be used assurfactants in the practice of the present disclosure include neutraland/or anionic/cationic excipients. Accordingly, suitable charged lipidsinclude, without limitation, phosphatidylcholines (lecithin), and thelike. Detergents will typically be a nonionic, anionic, cationic oramphoteric surfactant. Examples of suitable surfactants include, forexample, Tergitol® and Triton® surfactants (Union Carbide Chemicals andPlastics); polyoxyethylenesorbitans, e.g., TWEEN® surfactants (AtlasChemical Industries); polysorbates; polyoxyethylene ethers, e.g. Brij;pharmaceutically acceptable fatty acid esters, e.g., lauryl sulfate andsalts thereof; ampiphilic surfactants (glycerides, etc.); Gelucire®s(saturated polyglycolized glyceride (e.g., Gattefosse brand)); and likematerials. Surfactants, which can include one or more suitablesurfactant material, can be present in the compositions of the presentdisclosure at from about 0.01 to about 5 percent by weight relative tothe total weight of the composition (wt %), e.g., at from about 0.1 toabout 5 wt %, or at from about 0.1 to about 3 wt %. In some embodiments,a surfactant is present in the compositions of the present disclosure atabout 0.1 wt %, about 0.5 wt %, about 1 wt %, about 2 wt %, about 3 wt%, about 4 wt %, or about 5 wt %.

In some embodiments, a suitable surfactant for incorporation into thecompositions of the present disclosure includes one or more Gelucire®s(saturated polyglycolized glycerides). Suitable Gelucire®s include,e.g., Gelucire® 44/14 (lauroyl polyoxylglycerides) and Gelucire® 50/13(stearoyl polyoxylglycerides). Accordingly, in some embodiments, aGelucire®, e.g., Gelucire® 44/14, Gelucire® 50/13, or a combinationthereof, is present the compositions of the present disclosure at fromabout 0.01 to about 5 percent by weight relative to the total weight ofthe composition (wt %), e.g., at from about 0.1 to about 5 wt %, or atfrom about 0.1 to about 3 wt %. In some embodiments, a Gelucire®, e.g.,Gelucire® 44/14, Gelucire® 50/13, or a combination thereof, is presentin the compositions of the present disclosure at about 0.1 wt %, about0.5 wt %, about 1 wt %, about 2 wt %, about 3 wt %, about 4 wt %, orabout 5 wt %.

Exemplary Compositions

With reference to the various components discussed above, exemplarycompositions are now described.

In some embodiments a composition is provided which includes apharmacologically active agent; about 35% by weight to about 45% byweight, based on total weight of the composition, of a high viscosityliquid carrier material (HVLCM) having a viscosity of at least 5000 cPat 37° C. that does not crystallize neat at 25° C. and 1 atmosphere;about 31% by weight to about 45% by weight, based on total weight of thecomposition, of a solvent; about 2% by weight to about 10% by weight,based on total weight of the composition, of a rheology modifier; and acellulose acetate butyrate. Optionally, the composition may be providedwithin a capsule having a water content of less than about 10% byweight, e.g., an HPMC capsule having a water content of less than about10% by weight, e.g., less than about 5% by weight.

In some embodiments, a composition is provided which includes apharmacologically active agent; about 35% by weight to about 45% byweight, based on total weight of the composition, of sucrose acetateisobutyrate (SAIB); about 31% by weight to about 45% by weight, based ontotal weight of the composition, of triacetin; about 2% by weight toabout 10% by weight, based on total weight of the composition, ofisopropyl myristate (IPM); and about 4% to about 6% of a celluloseacetate butyrate (CAB), based on total weight of the composition.Optionally, the composition may be provided within a capsule having awater content of less than about 10% by weight, e.g., an HPMC capsulehaving a water content of less than about 10% by weight, e.g., less thanabout 5% by weight.

In some embodiments, a composition is provided which includes apharmacologically active agent; a high viscosity liquid carrier material(HVLCM) having a viscosity of at least 5000 cP at 37° C. that does notcrystallize neat at 25° C. and 1 atmosphere; a solvent; about 2% byweight to about 10% by weight, based on total weight of the composition,of a rheology modifier; and a cellulose acetate butyrate (CAB), whereinthe HVLCM and the solvent are present in the composition at a ratio ofabout 1.3:1 to about 1:1. Optionally, the composition may be providedwithin a capsule having a water content of less than about 10% byweight, e.g., an HPMC capsule having a water content of less than about10% by weight, e.g., less than about 5% by weight.

In some embodiments, a composition is provided which includes apharmacologically active agent; a high viscosity liquid carrier material(HVLCM) having a viscosity of at least 5000 cP at 37° C. that does notcrystallize neat at 25° C. and 1 atmosphere; a solvent; a rheologymodifier; and a cellulose acetate butyrate (CAB), wherein the HVLCM, thesolvent and the rheology modifier are present in the composition at aratio of about 1.3:1.0:0.3 to about 1.0:1.0:0.05. Optionally, thecomposition may be provided within a capsule having a water content ofless than about 10% by weight, e.g., an HPMC capsule having a watercontent of less than about 10% by weight, e.g., less than about 5% byweight.

In some embodiments, compositions are provided which provide specificadvantages relative to a reference composition, e.g., ReferenceFormulation A as described in Example 1 below. Accordingly, in someembodiments a composition is provided which includes a pharmacologicallyactive agent; a high viscosity liquid carrier material (HVLCM) having aviscosity of at least 5000 cP at 37° C. that does not crystallize neatat 25° C. and 1 atmosphere; a solvent; a rheology modifier; and acellulose acetate butyrate (CAB), wherein the HVLCM, the solvent and therheology modifier are present in the composition at a ratio sufficientto increase reproducibility of release relative to Reference FormulationA when assayed in a USP Apparatus 2 dissolution tester modified to havea 20-mesh basket for containing the composition. Optionally, thecomposition may be provided within a capsule having a water content ofless than about 10% by weight, e.g., an HPMC capsule having a watercontent of less than about 10% by weight, e.g., less than about 5% byweight.

In some embodiments, an increase in the reproducibility of release mayrefer to a reduction or decrease in a storage time-dependent change inan in vitro release profile of a composition. In such embodiments, thereproducibility of release for the composition may be determinedrelative to Reference Formulation A, which exhibits more than 10% meandrug release decline, a similarity factor (f₂) of less than 50, whenstored at 40° C./75% RH for a one month period of time relative to itsinitial release profile.

“Similarity factor” (f₂) as used herein refers to a logarithmicreciprocal square root transformation of one plus the mean squared (theaverage sum of squares) differences of drug percent dissolved betweenthe test and the reference products. In other words, the similarityfactor (f₂) is a logarithmic transformation of the sum-squared error ofdifferences between the test T_(t) and reference products R_(t) over alltime points. It represents the closeness of two comparativecompositions. Generally similarity factor in the range of 50-100 isacceptable according to the US FDA. f₂ may be calculated as follows:f₂=50*log {[1+(1/n)Σ_(t=1)*n(R_(t)−T_(t))²]^(−0.5)*100}, where R_(t) andT_(t) are the cumulative percentage dissolved at each of the selected ntime points of the reference and test product respectively.

In some embodiments, an increase in the reproducibility of release mayrefer to a reduction or decrease in inter-capsule variability at aparticular time point. In such embodiments, a decrease in inter-capsulevariability may be evidenced by a % RSD of less than about 15%, e.g.,less than about 10%, or less than about 5% at the particular time point,e.g., t=2 hr or t=3 hr. % RSD may be calculated as follows: %RSD=((SD/mean)×100). In some embodiments, a decrease in inter-capsulevariability may be evidenced by a % RSD of from about 15% to about 1%,e.g., from about 10% to about 1%, or from about 5% to about 1%.

Suitable in vitro dissolution test conditions for determining atime-dependent change in an in vitro release profile of a composition orinter-capsule variability of a composition, e.g., an oxycodone orhydrocodone containing composition are as follows: a USP Apparatus 2dissolution tester modified to include a 20 mesh screen hanging basketto hold the test article is utilized with dissolution medium containing1000 ml 0.1 N HCl with 0.5% (w/w) SDS. The dissolution medium ismaintained at 37° C. with stirring with 100 rpm paddle speed over thecourse of a 24 hour dissolution test. Standard sampling time points of0.5, 2, 3, 6, 12 and 24 hours are utilized. A 1 mL sample is taken ateach time point and assayed using reverse-phase HPLC at 240 nmwavelength with a mobile phase including 0.35% (w/v) SDS/0.7% (v/v)acetic acid/44% (v/v) acetonitrile in water. Where the dissolution testis used to determining a time-dependent change in an in vitro releaseprofile of a composition, the composition may be stored for a suitableperiod of time prior to testing, e.g., the composition may be stored at25° C./60% relative humidity (RH) for from 1 to 6 months or at 40°C./75% RH for from 1 to 6 months. A suitable number of capsules percomposition tested may be, e.g., 12 capsules.

For compositions including amphetamine, the following dissolutiontesting protocol may be utilized: 2-phase dissolution medium is utilizedin a USP Apparatus 2. Capsules are placed in stainless steel (316SS)wire spiral capsule sinkers for dissolution testing. The dissolutionparameters are as follows: Dissolution medium: 750 ml 0.1N HCl for thefirst 2 hours, with the addition of 200 ml 0.19M phosphate buffer toachieve a final pH of 6.0; Paddle speed: 50 rpm; Vessel temperature: 37°C. Sampling time points: 0.25, 0.5, 1, 1.5, 2, 3, 6, 9, 12 and 24 hours.Sampling volume: 1 mL. Suitable HPLC parameters are as follows: Mobilephase A: 5 mM 1-Decanesulfonic acid, sodium salt, 5 mM sodium phosphatemonobasic, pH 2.5; Mobile phase B: 100% acetonitrile; Mobile phase: 67%Mobile phase A and 33% Mobile phase B; 210 nm wavelength. A suitablenumber of capsules per composition tested may be, e.g., 6 capsules.

For compositions including methylphenidate, the following dissolutiontesting protocol may be utilized: 2-phase dissolution medium is utilizedin a USP Apparatus 2. Capsules are placed in stainless steel (316SS)wire spiral capsule sinkers for dissolution testing. The dissolutionparameters are as follows: Dissolution medium: 750 ml 0.1N HCl for thefirst 2 hours, with the addition of 200 ml 0.19M phosphate buffer toachieve a final pH of 6.0; Paddle speed: 50 rpm; Vessel temperature: 37°C. Sampling time points: 0.25, 0.5, 1, 1.5, 2, 3, 6, 9, 12 and 24 hours.Sampling volume: 1 mL. Suitable HPLC parameters are as follows: Mobilephase A: 5 mM 1-Decanesulfonic acid, sodium salt, 5 mM sodium phosphatemonobasic, pH 2.5; Mobile phase B: 100% acetonitrile; Mobile phase: 71%Mobile phase A and 29% Mobile phase B; 210 nm wavelength.

In some embodiments, a composition is provided which includes: apharmacologically active agent; a high viscosity liquid carrier material(HVLCM) having a viscosity of at least 5000 cP at 37° C. that does notcrystallize neat at 25° C. and 1 atmosphere; a solvent; a rheologymodifier; and a cellulose acetate butyrate, wherein the composition isencapsulated within a hydroxypropylmethylcellulose capsule, and whereinthe composition within the capsule includes less than 5% water byweight, based on total weight of the composition within the capsule.

In some embodiments, a composition is provided which includes: apharmacologically active agent; and means for reducing a storagetime-dependent change in an in vitro release profile of a compositionrelative to Reference Formulation A. Optionally, the composition may beprovided within a capsule having a water content of less than about 10%by weight, e.g., an HPMC capsule having a water content of less thanabout 10% by weight, e.g., less than about 5% by weight.

In some embodiments, a composition is provided which includes: oxycodoneat about 5% by weight relative to the total weight of the composition;and means for reducing a storage time-dependent change in an in vitrorelease profile of the composition Relative to Ref. Formulation A.Optionally, the composition may be provided within a capsule having awater content of less than about 10% by weight, e.g., an HPMC capsulehaving a water content of less than about 10% by weight, e.g., less thanabout 5% by weight.

In some embodiments, a composition is provided which includes: apharmacologically active agent; a high viscosity liquid carrier material(HVLCM) having a viscosity of at least 5000 cP at 37° C. that does notcrystallize neat at 25° C. and 1 atmosphere; a solvent; a networkformer; and a mineral particle, wherein the mineral particle is presentin the composition in an amount from about 2.4% by weight to about 5.4%by weight relative to the total weight of the composition. Optionally,the composition may be provided within a capsule having a water contentof less than about 10% by weight, e.g., an HPMC capsule having a watercontent of less than about 10% by weight, e.g., less than about 5% byweight.

In some embodiments, a composition is provided which includes: anopioid; sucrose acetate isobutyrate (SAIB); triacetin; isopropylmyristate (IPM); cellulose acetate butyrate (CAB); hydroxyethylcellulose (HEC); and silicon dioxide, wherein the silicon dioxide ispresent in the composition in an amount from about 2.4% by weight toabout 5.4% by weight relative to the total weight of the composition.Optionally, the composition may be provided within a capsule having awater content of less than about 10% by weight, e.g., an HPMC capsulehaving a water content of less than about 10% by weight, e.g., less thanabout 5% by weight.

In some embodiments, a composition is provided which includes:oxycodone; about 35% by weight to about 45% sucrose acetate isobutyrate(SAIB) relative to the total weight of the composition; about 31% byweight to about 45% of triacetin relative to the total weight of thecomposition; about 2% by weight to about 10% by weight of isopropylmyristate (IPM) relative to the total weight of the composition; about4% to about 6% by weight of cellulose acetate butyrate (CAB) relative tothe total weight of the composition; about 5% by weight to about 6% byweight of hydroxyethyl cellulose (HEC) relative to the total weight ofthe composition; and about 2.4% by weight to about 5.4% by weight ofsilicon dioxide relative to the total weight of the composition.Optionally, the composition may be provided within a capsule having awater content of less than about 10% by weight, e.g., an HPMC capsulehaving a water content of less than about 10% by weight, e.g., less thanabout 5% by weight.

In some embodiments, a composition is provided which includes:oxycodone; about 39% by weight to about 41% sucrose acetate isobutyrate(SAIB) relative to the total weight of the composition; about 38% byweight to about 41% of triacetin relative to the total weight of thecomposition; about 2% by weight to about 3% by weight of isopropylmyristate (IPM) relative to the total weight of the composition; about4% to about 6% by weight of cellulose acetate butyrate (CAB) relative tothe total weight of the composition; about 5% by weight to about 6% byweight of hydroxyethyl cellulose (HEC) relative to the total weight ofthe composition; and about 2.5% by weight to about 3.2% by weight ofsilicon dioxide relative to the total weight of the composition.Optionally, the composition may be provided within a capsule having awater content of less than about 10% by weight, e.g., an HPMC capsulehaving a water content of less than about 10% by weight, e.g., less thanabout 5% by weight.

In some embodiments, a composition is provided which includes: about 5%by weight of oxycodone relative to the total weight of the composition;about 39% by weight to about 41% sucrose acetate isobutyrate (SAIB)relative to the total weight of the composition; about 38% by weight toabout 41% of triacetin relative to the total weight of the composition;about 2% by weight to about 3% by weight of isopropyl myristate (IPM)relative to the total weight of the composition; about 4% to about 6% byweight of cellulose acetate butyrate (CAB) relative to the total weightof the composition; about 5% by weight to about 6% by weight ofhydroxyethyl cellulose (HEC) relative to the total weight of thecomposition; and about 2.5% by weight to about 3.2% by weight of silicondioxide relative to the total weight of the composition. Optionally, thecomposition may be provided within a capsule having a water content ofless than about 10% by weight, e.g., an HPMC capsule having a watercontent of less than about 10% by weight, e.g., less than about 5% byweight.

In some embodiments, a composition is provided which includes: oxycodoneat about 5% by weight relative to the total weight of the composition;sucrose acetate isobutyrate (SAIB) at about 40% by weight relative tothe total weight of the composition; triacetin at about 39% by weightrelative to the total weight of the composition; isopropyl myristate(IPM) at about 2.5% by weight relative to the total weight of thecomposition; cellulose acetate butyrate (CAB) at about 4.5% by weightrelative to the total weight of the composition; hydroxyethyl cellulose(HEC) at about 5.5% by weight relative to the total weight of thecomposition; and silicon dioxide at about 2.9% by weight relative to thetotal weight of the composition. Optionally, the composition may beprovided within a capsule having a water content of less than about 10%by weight, e.g., an HPMC capsule having a water content of less thanabout 10% by weight, e.g., less than about 5% by weight.

In some embodiments, a composition is provided which includes: oxycodoneat about 5% by weight relative to the total weight of the composition;sucrose acetate isobutyrate (SAIB) at about 40% by weight relative tothe total weight of the composition; triacetin at about 39% by weightrelative to the total weight of the composition; isopropyl myristate(IPM) at about 2.5% by weight relative to the total weight of thecomposition; cellulose acetate butyrate (CAB) at about 4.5% by weightrelative to the total weight of the composition; hydroxyethyl cellulose(HEC) at about 5.5% by weight relative to the total weight of thecomposition; and silicon dioxide at about 2.9% by weight relative to thetotal weight of the composition, wherein the composition is encapsulatedwithin a hydroxypropylmethylcellulose (HPMC) capsule.

In some embodiments, a composition is provided which includes: apharmacologically active agent; a high viscosity liquid carrier material(HVLCM) having a viscosity of at least 5000 cP at 37° C. that does notcrystallize neat at 25° C. and 1 atmosphere; a solvent; a networkformer; and a mineral particle, wherein the HVLCM, the solvent, thenetwork former, and the mineral particle are present in a ratiosufficient to reduce a storage time-dependent change in an in vitrorelease profile of a composition relative to Reference Formulation A.Optionally, the composition may be provided within a capsule having awater content of less than about 10% by weight, e.g., an HPMC capsulehaving a water content of less than about 10% by weight, e.g., less thanabout 5% by weight.

In some embodiments, a composition is provided which includes: apharmacologically active agent; a high viscosity liquid carrier material(HVLCM) having a viscosity of at least 5000 cP at 37° C. that does notcrystallize neat at 25° C. and 1 atmosphere; a solvent; a networkformer; and a mineral particle, wherein the HVLCM, the solvent, thenetwork former, and the mineral particle are present in a ratiosufficient to reduce inter-capsule variability in an in vitro releaseprofile of the composition relative to Reference Formulation A, whenassayed in a USP Apparatus 2 dissolution tester modified to have a20-mesh basket for containing the composition. Optionally, thecomposition may be provided within a capsule having a water content ofless than about 10% by weight, e.g., an HPMC capsule having a watercontent of less than about 10% by weight, e.g., less than about 5% byweight.

In some embodiments, a composition is provided which includes: apharmacologically active agent; a high viscosity liquid carrier material(HVLCM) having a viscosity of at least 5000 cP at 37° C. that does notcrystallize neat at 25° C. and 1 atmosphere; a solvent; a networkformer; and a mineral particle, wherein the HVLCM, the solvent, thenetwork former, and the mineral particle are present in a ratiosufficient to provide an in vitro release profile characterized by aninter-capsule variability having a % RSD of less than or equal to 10% att=2 hr as determined by an in vitro dissolution assay using a USPApparatus 2 dissolution tester modified to have a 20-mesh basket forcontaining the composition. Optionally, the composition may be providedwithin a capsule having a water content of less than about 10% byweight, e.g., an HPMC capsule having a water content of less than about10% by weight, e.g., less than about 5% by weight.

In some embodiments, a composition is provided which includes: oxycodoneat about 5% by weight relative to the total weight of the composition;sucrose acetate isobutyrate (SAIB); triacetin; isopropyl myristate(IPM); cellulose acetate butyrate (CAB); hydroxyethyl cellulose (HEC);and silicon dioxide, wherein the sucrose acetate isobutyrate (SAIB),triacetin, isopropyl myristate (IPM), cellulose acetate butyrate (CAB),hydroxyethyl cellulose (HEC), and silicon dioxide, are present in aratio sufficient to reduce a storage time-dependent change in an invitro release profile of the composition relative to ReferenceFormulation A. Optionally, the composition may be provided within acapsule having a water content of less than about 10% by weight, e.g.,an HPMC capsule having a water content of less than about 10% by weight,e.g., less than about 5% by weight.

In some embodiments, a composition is provided which includes: oxycodoneat about 5% by weight relative to the total weight of the composition;sucrose acetate isobutyrate (SAIB); triacetin; isopropyl myristate(IPM); cellulose acetate butyrate (CAB); hydroxyethyl cellulose (HEC);and silicon dioxide, wherein the sucrose acetate isobutyrate (SAIB),triacetin, isopropyl myristate (IPM), cellulose acetate butyrate (CAB),hydroxyethyl cellulose (HEC), and silicon dioxide, are present in aratio sufficient to reduce inter-capsule variability relative toFormulation A when assayed in a USP Apparatus 2 dissolution testermodified to have a 20-mesh basket for containing the composition.Optionally, the composition may be provided within a capsule having awater content of less than about 10% by weight, e.g., an HPMC capsulehaving a water content of less than about 10% by weight, e.g., less thanabout 5% by weight.

In some embodiments, a composition is provided which includes: oxycodoneat about 5% by weight relative to the total weight of the composition;sucrose acetate isobutyrate (SAIB); triacetin; isopropyl myristate(IPM); cellulose acetate butyrate (CAB); hydroxyethyl cellulose (HEC);and silicon dioxide, wherein the sucrose acetate isobutyrate (SAIB),triacetin, isopropyl myristate (IPM), cellulose acetate butyrate (CAB),hydroxyethyl cellulose (HEC), and silicon dioxide, are present in aratio sufficient to provide an in vitro release profile characterized byan inter-capsule variability having a % RSD of less than 10% at t=2 hras determined by an in vitro dissolution assay using a USP Apparatus 2dissolution tester modified to have a 20-mesh basket for containing thecomposition. Optionally, the composition may be provided within acapsule having a water content of less than about 10% by weight, e.g.,an HPMC capsule having a water content of less than about 10% by weight,e.g., less than about 5% by weight.

In some embodiments, a composition is provided which includes: apharmacologically active agent; and combined amounts of a high viscosityliquid carrier material (HVLCM) having a viscosity of at least 5000 cPat 37° C. that does not crystallize neat at 25° C. and 1 atmosphere, asolvent, a rheology modifier, silicon dioxide, and a cellulose acetatebutyrate, wherein the combined amounts are sufficient to increasereproducibility of release with respect to inter-capsule variabilityrelative to Reference Formulation A when assayed in a USP Apparatus 2dissolution tester modified to have a 20-mesh basket for containing thecomposition. Optionally, the composition may be provided within acapsule having a water content of less than about 10% by weight, e.g.,an HPMC capsule having a water content of less than about 10% by weight,e.g., less than about 5% by weight.

In some embodiments, a composition is provided which includes: apharmacologically active agent; and combined amounts of a high viscosityliquid carrier material (HVLCM) having a viscosity of at least 5000 cPat 37° C. that does not crystallize neat at 25° C. and 1 atmosphere, asolvent, a rheology modifier, silicon dioxide, and a cellulose acetatebutyrate, wherein the combined amounts are sufficient to provide an invitro release profile characterized by an inter-capsule variabilityhaving a % RSD of less than 10% at t=2 hr as determined by an in vitrodissolution assay using a USP Apparatus 2 dissolution tester modified tohave a 20-mesh basket for containing the composition. Optionally, thecomposition may be provided within a capsule having a water content ofless than about 10% by weight, e.g., an HPMC capsule having a watercontent of less than about 10% by weight, e.g., less than about 5% byweight.

In some embodiments, a composition is provided which includes: apharmacologically active agent; and combined amounts of a high viscosityliquid carrier material (HVLCM) having a viscosity of at least 5000 cPat 37° C. that does not crystallize neat at 25° C. and 1 atmosphere, asolvent, a rheology modifier, silicon dioxide, and a cellulose acetatebutyrate, wherein the combined amounts are sufficient to increasereproducibility of release with respect to storage time relative toReference Formulation A when assayed in a USP Apparatus 2 dissolutiontester modified to have a 20-mesh basket for containing the composition.Optionally, the composition may be provided within a capsule having awater content of less than about 10% by weight, e.g., an HPMC capsulehaving a water content of less than about 10% by weight, e.g., less thanabout 5% by weight.

Methods of Making, Encapsulating and Administering

Once constituents have been selected to produce a composition (e.g., anextended release composition) in accordance with the present disclosure,a liquid pharmaceutical composition can be prepared by simply mixing,for example a HVLCM, a rheology modifier, a network former, the activeagent, a solvent and any additional additives. The compositions of thepresent disclosure are produced as liquid mixtures, and have a number ofexcipient ingredients that are in solution, suspension, or in partialsolution within the final composition. Suitable methods for compoundingor manufacturing the compositions make use of typicalpharmaceutical/chemical mixing and handling apparatus and techniques.Since the liquid compositions of the present disclosure are formed froma number of highly viscous liquids and solids, they may have high finalviscosities. Accordingly, the specific equipment and techniques employedin the manufacture of such compositions may be selected so as toaccommodate such material demands. In particular, various excipients,such as network formers, may be added to the composition mixture in thesolid or semi-solid state, and as such they may be screened or otherwisesize-reduced prior to addition to a composition mixing apparatus. Othersolid excipients may require melting prior to addition to the liquidmixture. The HVLCM materials are very high viscosity liquid materials,however they tend to exhibit a dramatic reduction in viscosity withincreases in heat, and as such the mixing apparatus may be heated toaccommodate the addition of the HVLCM material or other similarmaterials. However, the mixing and processing conditions should takeinto account the final integrity of the composition and accordingly themixing conditions may be selected so as to have a low-sheer effect onthe composition, and/or to avoid any extended or pronounced excursionsinto high or low heat conditions. Once the composition has been properlycombined, an appropriate amount of the resulting liquid mixture can beplaced into a suitable capsule, such as a gelatin or HPMC capsule toprovide an oral pharmaceutical dosage form. Alternative liquidcompositions may include emulsifying the mixture in water, andintroducing this emulsion into a capsule.

An additional, exemplary composition preparation and encapsulationscheme is provided in FIG. 2.

In some embodiments, an oral dosage form is provided which is composedof a liquid composition containing the active agent and any additionalcomponents within an enclosure or capsule, e.g., a biodegradableenclosure or capsule, such as a capsule or a gelatin capsule (“gelcap”),wherein the capsule is made of a substance that degrades or otherwisedissociates when exposed to conditions present in the gastro-intestinaltract of a mammal. Capsules and gelcaps are well known in drug deliverytechnology and one of skill could select such a capsule as appropriatefor delivery of a particular active agent. Once the capsule hasdissolved or dissociated from the composition, the disclosedcompositions generally remains intact, especially for hydrophobiccompositions, and passes through the GI tract without emulsification orfragmentation.

Suitable capsules which may be utilized in connection with the disclosedcompositions include, but are not limited to hard-shelled capsules,soft-shelled capsules, and interlocking capsules.

In some embodiments a suitable capsule includes gelatin or syntheticpolymers such as hydroxyl ethyl cellulose and/or hydroxyl propylmethylcellulose. Gelcaps can be of the hard or soft variety, including, forexample, polysaccharide or hypromellose acetate succinate based caps(e.g., Vegicaps brand, available from Catalent). The capsule can also becoated with an enteric coating material such as AQIAT (Shin-Etsu) todelay release.

As discussed in the Examples below, certain time-dependent changes indrug release performance have been observed for Reference Formulation A.Without intending to be bound by any particular theory, it is believedthat reducing the amount of water available to the compositions of thepresent disclosure may minimize these effects. For example, by utilizingHPMC capsules (˜2-6% w/w water, e.g., 4-6% w/w water) instead of gelatincapsules (˜13-16% w/w water) the amount of water available to thecompositions may be reduced. Accordingly, in some embodiments, thecompositions of the present disclosure are specifically encapsulatedwithin capsules having lower water content than gelatin capsules, e.g.,water content of less than about 15% w/w, less than about 14% w/w, lessthan about 13% w/w, less than about 12% w/w, less than about 11% w/w,less than 10% w/w, less than about 9% w/w, less than about 8% w/w, lessthan about 7% w/w, less than about 6% w/w, less than about 5% w/w, lessthan about 4% w/w, less than about 3% w/w, less than about 2% w/w, orless than about 1% w/w. In some embodiments, the compositions of thepresent disclosure are encapsulated within capsules having a watercontent of from about 1% w/w to about 10% w/w, e.g., from about 1% w/wto about 9% w/w, from about 1% w/w to about 8% w/w, from about 1% w/w toabout 7% w/w, from about 1% w/w to about 6% w/w, from about 1% w/w toabout 5% w/w, from about 1% w/w to about 4% w/w, from about 1% w/w toabout 3% w/w, or from about 1% w/w to about 2% w/w. In some embodiments,the compositions of the present disclosure are encapsulated in capsuleshaving a water content less than about 1% w/w including, for example,from about 0.1% w/w to about 1% w/w, from about 0.2% w/w to about 0.8%w/w, from about 0.4% w/w to about 0.8% w/w, or from about 0.6% w/w toabout 0.8% w/w. Suitable HPMC capsules may include, for example,V-capS™, V-caps Plus™, Quali-V™, VegiCaps™, Embo Caps-Vg™, and HMPCcapsules provided by Baotou Capstech Co., Ltd, and Zhejiang LinFengCapsules Co. Ltd.

The water content of a capsule, composition, or composition incombination with a capsule, when provided within a capsule as describedin the present disclosure, may be determined by Karl Fischer titrationmethod as set forth in USP <921> Method 1C. In some embodiments, anAquaStar C3000 Karl Fischer Coulometric Titrator may be used inconnection with the disclosed titration method.

In some embodiments, a composition according to the present disclosureis one which has relatively low water content. For example, in someembodiments, a composition according to the present disclosure does notinclude more than about 5% water by weight, based on total weight of thecomposition. For example, the composition may include water at less thanabout 5% by weight, less than about 4% by weight, less than about 3% byweight, or less than about 2% by weight, based on the total weight ofthe composition. In some embodiments, a composition according to thepresent disclosure includes water at from about 1.0 to about 5.0% byweight, based on total weight of the composition, e.g., at from about1.0 to about 4.5% by weight, at from about 1.0 to about 3.0% by weight,at from about 1.0 to about 2.5% by weight, at from about 1.0 to about2.0% by weight, or at from about 1.0 to about 1.5% by weight, based ontotal weight of the composition. In some embodiments, a compositionaccording to the present disclosure includes water at about 1.0% byweight, about 1.5% by weight, about 2% by weight, about 2.5% by weight,about 3% by weight, about 3.5% by weight, about 4% by weight, about 4.5%by weight, or about 5% by weight, based on the total weight of thecomposition. In the above embodiments, each of the above compositionsmay be a composition which has been encapsulated within a capsule havinga water content of less than about 15% w/w (e.g., less than about 10%w/w or less than about 5% w/w), e.g., an HPMC capsule, and stored for aperiod of time, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, at25° C. and 60% relative humidity (RH), 30° C. and 65% RH, or 40° C. and75% RH.

The water content of a composition as described in the presentdisclosure may be determined by Karl Fischer titration method as setforth in USP <921> Method 1C. In some embodiments, an AquaStar C3000Karl Fischer Coulometric Titrator may be used in connection with thedisclosed titration method.

In some embodiments, the water content of the composition and thecapsule combined is less than about 5% by weight based on the totalweight of the composition and the capsule combined, e.g., less thanabout 4% by weight, less than about 3% by weight, or less than about 2%by weight based on the total weight of the composition and the capsulecombined. In some embodiments, the water content of the composition andthe capsule combined is from about 5% by weight to about 4% by weight,from about 4% by weight to about 3% by weight, from about 3% by weightto about 2% by weight, or from about 2% by weight to about 1% by weightbased on the total weight of the composition and the capsule combined.In some embodiments, the water content of the composition and thecapsule combined is about 1.0% by weight, about 1.5% by weight, about 2%by weight, about 2.5% by weight, about 3% by weight, about 3.5% byweight, about 4% by weight, about 4.5% by weight, or about 5% by weight,based on the total weight of the composition and the capsule combined.The water content of a composition and capsule combined as described inthe present disclosure may be determined by Karl Fischer titrationmethod as set forth in USP <921> Method 1C. In some embodiments, anAquaStar C3000 Karl Fischer Coulometric Titrator may be used inconnection with the disclosed titration method.

The time-dependent change in release performance may also be addressedby formulating the various components of the composition in specificconcentration ranges and/or at specific ratios for oral dosage forms.Accordingly, the present disclosure provides a method of orallyadministering a composition, including: reducing a time-dependent changein an in vitro release profile of a composition by formulating thecomposition to include, in addition to a pharmacologically active agent,about 35% by weight to about 45% by weight, based on total weight of thecomposition, of a high viscosity liquid carrier material (HVLCM) havinga viscosity of at least 5000 cP at 37° C. that does not crystallize neatat 25° C. and 1 atmosphere, about 31% by weight to about 45% by weight,based on total weight of the composition, of a solvent, about 2% byweight to about 10% by weight, based on total weight of the composition,of a rheology modifier, and a cellulose acetate butyrate; and orallyadministering the composition. Optionally, the composition may beprovided within a capsule having a water content of less than about 10%by weight, e.g., an HPMC capsule having a water content of less thanabout 10% by weight, e.g., less than about 5% by weight.

In some embodiments, the present disclosure provides a method ofreducing a time-dependent change in an in vitro release profile of apharmacologically active agent from a composition, wherein the methodincludes formulating the pharmacologically active agent with (a) a highviscosity liquid carrier material (HVLCM) having a viscosity of at least5000 cP at 37 C that does not crystallize neat at 25 C and 1 atmosphere,(b) a solvent, (c) a rheology modifier and (d) cellulose acetatebutyrate, such that the composition includes about 35% by weight toabout 45% by weight, based on total weight of the composition, of thehigh viscosity liquid carrier material (HVLCM) having a viscosity of atleast 5000 cP at 37 C that does not crystallize neat at 25 C and 1atmosphere, about 31% by weight to about 45% by weight, based on totalweight of the composition, of the solvent, about 2% by weight to about10% by weight, based on total weight of the composition, of the rheologymodifier, and the cellulose acetate butyrate. Optionally, thecomposition may be provided within a capsule having a water content ofless than about 10% by weight, e.g., an HPMC capsule having a watercontent of less than about 10% by weight, e.g., less than about 5% byweight.

In some embodiments, the present disclosure provides a use of (a) a highviscosity liquid carrier material (HVLCM) having a viscosity of at least5000 cP at 37 C that does not crystallize neat at 25 C and 1 atmosphere,(b) a solvent, (c) a rheology modifier and (d) cellulose acetatebutyrate, for reducing a time-dependent change in an in vitro releaseprofile of a pharmacologically active agent from a composition, whereinthe use includes formulating the pharmacologically active agent with (a)the high viscosity liquid carrier material (HVLCM) having a viscosity ofat least 5000 cP at 37 C that does not crystallize neat at 25 C and 1atmosphere, (b) the solvent, (c) the rheology modifier and (d) celluloseacetate butyrate, thereby providing a composition that includes about35% by weight to about 45% by weight, based on total weight of thecomposition, of the high viscosity liquid carrier material (HVLCM)having a viscosity of at least 5000 cP at 37 C that does not crystallizeneat at 25 C and 1 atmosphere, about 31% by weight to about 45% byweight, based on total weight of the composition, of the solvent, about2% by weight to about 10% by weight, based on total weight of thecomposition, of the rheology modifier, and the cellulose acetatebutyrate. Optionally, the composition may be provided within a capsulehaving a water content of less than about 10% by weight, e.g., an HPMCcapsule having a water content of less than about 10% by weight, e.g.,less than about 5% by weight.

In some embodiments, the present disclosure provides a method of orallyadministering a composition, including: reducing a time-dependent changein an in vitro release profile of a composition by formulating thecomposition to include, in addition to a pharmacologically active agent,a high viscosity liquid carrier material (HVLCM) having a viscosity ofat least 5000 cP at 37° C. that does not crystallize neat at 25° C. and1 atmosphere, a solvent; about 2% by weight to about 10% by weight,based on total weight of the composition, of a rheology modifier, and acellulose acetate butyrate (CAB), wherein the HVLCM and the solvent arepresent in the composition at a ratio of about 1.3:1.0 to about 1.0:1.0;and orally administering the composition. Optionally, the compositionmay be provided within a capsule having a water content of less thanabout 10% by weight, e.g., an HPMC capsule having a water content ofless than about 10% by weight, e.g., less than about 5% by weight.

In some embodiments, the present disclosure provides a method of orallyadministering a composition, including: reducing a time-dependent changein an in vitro release profile of a composition by formulating thecomposition to include, in addition to a pharmacologically active agent,a high viscosity liquid carrier material (HVLCM) having a viscosity ofat least 5000 cP at 37° C. that does not crystallize neat at 25° C. and1 atmosphere; a solvent; a rheology modifier; and a cellulose acetatebutyrate (CAB), wherein the HVLCM, the solvent and the rheology modifierare present in the composition at a ratio of about 1.3:1.0:0.3 to about1.0:1.0:0.05; and orally administering the composition. Optionally, thecomposition may be provided within a capsule having a water content ofless than about 10% by weight, e.g., an HPMC capsule having a watercontent of less than about 10% by weight, e.g., less than about 5% byweight.

In some embodiments, the present disclosure provides a method of orallyadministering a composition, including: reducing a time-dependent changein an in vitro release profile of a composition by formulating thecomposition to include, in addition to a pharmacologically active agent,a high viscosity liquid carrier material (HVLCM) having a viscosity ofat least 5000 cP at 37° C. that does not crystallize neat at 25° C. and1 atmosphere; a solvent; a rheology modifier; and a cellulose acetatebutyrate (CAB), wherein the HVLCM, the solvent and the rheology modifierare present in the composition at a ratio sufficient to increasereproducibility of release relative to Reference Formulation A whenassayed in a USP Apparatus 2 dissolution tester modified to have a20-mesh basket for containing the composition; and orally administeringthe composition. Optionally, the composition may be provided within acapsule having a water content of less than about 10% by weight, e.g.,an HPMC capsule having a water content of less than about 10% by weight,e.g., less than about 5% by weight.

In some embodiments, the present disclosure provides a method of orallyadministering a composition, including: reducing a storagetime-dependent change in a release profile of a composition byformulating the composition to include, in addition to apharmacologically active agent, means for the reducing a storagetime-dependent change in a release profile of the composition relativeto Reference Formulation A. Optionally, the composition may be providedwithin a capsule having a water content of less than about 10% byweight, e.g., an HPMC capsule having a water content of less than about10% by weight, e.g., less than about 5% by weight.

In some embodiments, the present disclosure provides a method fortreating pain in a subject, the method including: orally administeringto the subject a composition including an opioid; a high viscosityliquid carrier material (HVLCM) having a viscosity of at least 5000 cPat 37° C. that does not crystallize neat at 25° C. and 1 atmosphere; asolvent; a network former; and silicon dioxide, wherein the silicondioxide is present in the composition in an amount from about 2.4% byweight to about 5.4% by weight relative to the total weight of thecomposition, wherein the composition is formulated for oraladministration, and one or more symptoms or signs associated with thesubject's pain is alleviated. Optionally, the composition may beprovided within a capsule having a water content of less than about 10%by weight, e.g., an HPMC capsule having a water content of less thanabout 10% by weight, e.g., less than about 5% by weight.

In some embodiments, the present disclosure provides a method fortreating pain in a subject, the method including: orally administeringto the subject a composition including an opioid; sucrose acetateisobutyrate (SAIB); triacetin; isopropyl myristate (IPM); celluloseacetate butyrate (CAB); hydroxyethyl cellulose (HEC); and silicondioxide, wherein the silicon dioxide is present in the composition in anamount from about 2.4% by weight to about 5.4% by weight relative to thetotal weight of the composition, wherein the composition is formulatedfor oral administration, and one or more symptoms or signs associatedwith the subject's pain is alleviated. Optionally, the composition maybe provided within a capsule having a water content of less than about10% by weight, e.g., an HPMC capsule having a water content of less thanabout 10% by weight, e.g., less than about 5% by weight.

In some embodiments, the present disclosure provides a method fortreating pain in a subject, the method including: orally administeringto the subject a composition including oxycodone; about 35% by weight toabout 45% sucrose acetate isobutyrate (SAIB) relative to the totalweight of the composition; about 31% by weight to about 45% of triacetinrelative to the total weight of the composition; about 2% by weight toabout 10% by weight of isopropyl myristate (IPM) relative to the totalweight of the composition; about 4% to about 6% by weight of celluloseacetate butyrate (CAB) relative to the total weight of the composition;about 5% by weight to about 6% by weight of hydroxyethyl cellulose (HEC)relative to the total weight of the composition; and about 2.4% byweight to about 5.4% by weight of silicon dioxide relative to the totalweight of the composition, wherein one or more symptoms or signsassociated with the subject's pain is alleviated. Optionally, thecomposition may be provided within a capsule having a water content ofless than about 10% by weight, e.g., an HPMC capsule having a watercontent of less than about 10% by weight, e.g., less than about 5% byweight.

In some embodiments, the present disclosure provides a method fortreating pain in a subject, the method including: orally administeringto the subject a composition including oxycodone; about 39% by weight toabout 41% sucrose acetate isobutyrate (SAIB) relative to the totalweight of the composition; about 38% by weight to about 41% of triacetinrelative to the total weight of the composition; about 2% by weight toabout 3% by weight of isopropyl myristate (IPM) relative to the totalweight of the composition; about 4% to about 6% by weight of celluloseacetate butyrate (CAB) relative to the total weight of the composition;about 5% by weight to about 6% by weight of hydroxyethyl cellulose (HEC)relative to the total weight of the composition; and about 2.5% byweight to about 3.2% by weight of silicon dioxide relative to the totalweight of the composition, wherein one or more symptoms or signsassociated with the subject's pain is alleviated. Optionally, thecomposition may be provided within a capsule having a water content ofless than about 10% by weight, e.g., an HPMC capsule having a watercontent of less than about 10% by weight, e.g., less than about 5% byweight.

In some embodiments, the present disclosure provides a method fortreating pain in a subject, the method including: orally administeringto the subject a composition including about 5% by weight of oxycodonerelative to the total weight of the composition; about 39% by weight toabout 41% sucrose acetate isobutyrate (SAIB) relative to the totalweight of the composition; about 38% by weight to about 41% of triacetinrelative to the total weight of the composition; about 2% by weight toabout 3% by weight of isopropyl myristate (IPM) relative to the totalweight of the composition; about 4% to about 6% by weight of celluloseacetate butyrate (CAB) relative to the total weight of the composition;about 5% by weight to about 6% by weight of hydroxyethyl cellulose (HEC)relative to the total weight of the composition; and about 2.5% byweight to about 3.2% by weight of silicon dioxide relative to the totalweight of the composition, wherein one or more symptoms or signsassociated with the subject's pain is alleviated. Optionally, thecomposition may be provided within a capsule having a water content ofless than about 10% by weight, e.g., an HPMC capsule having a watercontent of less than about 10% by weight, e.g., less than about 5% byweight.

In some embodiments, the present disclosure provides a method fortreating pain in a subject, the method including: orally administeringto the subject a composition including oxycodone at about 5% by weightrelative to the total weight of the composition; sucrose acetateisobutyrate (SAIB) at about 40% by weight relative to the total weightof the composition; triacetin at about 39% by weight relative to thetotal weight of the composition; isopropyl myristate (IPM) at about 2.5%by weight relative to the total weight of the composition; celluloseacetate butyrate (CAB) at about 4.5% by weight relative to the totalweight of the composition; hydroxyethyl cellulose (HEC) at about 5.5% byweight relative to the total weight of the composition; and silicondioxide, wherein the silicon dioxide is present in the composition atabout 2.9% by weight relative to the total weight of the composition,wherein the composition is formulated for oral administration, and oneor more symptoms or signs associated with the subject's pain isalleviated. Optionally, the composition may be provided within a capsulehaving a water content of less than about 10% by weight, e.g., an HPMCcapsule having a water content of less than about 10% by weight, e.g.,less than about 5% by weight.

In some embodiments, the present disclosure provides a method of orallyadministering a composition, including: improving reproducibility of anin vitro release profile of a composition by including about 2.4% byweight to about 5.4% by weight, relative to the total weight of thecomposition, of mineral particle in the composition, wherein thecomposition also includes a pharmacologically active agent, a highviscosity liquid carrier material (HVLCM) having a viscosity of at least5000 cP at 37° C. that does not crystallize neat at 25° C. and 1atmosphere, a solvent, and a network former; and orally administeringthe composition. Optionally, the composition may be provided within acapsule having a water content of less than about 10% by weight, e.g.,an HPMC capsule having a water content of less than about 10% by weight,e.g., less than about 5% by weight.

In some embodiments, the present disclosure provides a method of orallyadministering a composition, including: decreasing the variability of anin vitro release profile of a composition by including about 2.4% byweight to about 5.4% by weight, relative to the total weight of thecomposition, of mineral particle in the composition, wherein thecomposition also includes a pharmacologically active agent, a highviscosity liquid carrier material (HVLCM) having a viscosity of at least5000 cP at 37° C. that does not crystallize neat at 25° C. and 1atmosphere, a solvent, and a network former; and orally administeringthe composition. Optionally, the composition may be provided within acapsule having a water content of less than about 10% by weight, e.g.,an HPMC capsule having a water content of less than about 10% by weight,e.g., less than about 5% by weight.

In some embodiments, the present disclosure provides a method of orallyadministering an encapsulated composition, including: forming acomposition including: a pharmacologically active agent, a highviscosity liquid carrier material (HVLCM) having a viscosity of at least5000 cP at 37° C. that does not crystallize neat at 25° C. and 1atmosphere, a solvent, a network former, and a mineral particle, whereinthe mineral particle is present in the composition in an amount fromabout 2.4% by weight to about 5.4% by weight relative to the totalweight of the composition; improving an in vitro release profile of thecomposition by encapsulating the composition within a capsule includinghydroxypropyl methylcellulose to form an encapsulated composition; andorally administering the encapsulated composition.

In some embodiments, the present disclosure provides a method of orallyadministering an encapsulated composition, including: forming acomposition including: a pharmacologically active agent, a highviscosity liquid carrier material (HVLCM) having a viscosity of at least5000 cP at 37° C. that does not crystallize neat at 25° C. and 1atmosphere, a solvent, a network former, and a mineral particle, whereinthe mineral particle is present in the composition in an amount fromabout 2.4% by weight to about 5.4% by weight relative to the totalweight of the composition; reducing exposure of the composition to waterby encapsulating the composition within a capsule includinghydroxypropyl methylcellulose to form an encapsulated composition; andorally administering the encapsulated composition.

In certain embodiments, the compositions of the present disclosure maybe formulated so as to produce particular controlled plasma levels of anactive agent over a particular period, e.g., to maintain a plasma levelwithin an appropriate therapeutic range. An appropriate therapeuticrange will vary depending on the active agent, but can range fromfemtogram/mL levels up to above microgram/mL levels for a desired periodof time. For example, a single dose of a composition disclosed hereinmay result in maintenance of plasma levels of greater than 5 ng/mL for aperiod of greater than 8 hours. In other embodiments, the plasma levelachieved using a single dose may be greater than about 5 ng/mL for aperiod of greater than about 10 hours, greater than about 12 hours,greater than about 14 hours, greater than about 16 hours, greater thanabout 18 hours, or greater than about 20 hours. In yet otherembodiments, the plasma level achieved using a single dose may begreater than about 5 ng/mL, greater than about 10 ng/mL, greater thanabout 15 ng/mL, greater than about 20 ng/mL, greater than about 30ng/mL, greater than about 40 ng/mL, or greater than about 50 ng/mL for aperiod of about 4, about 8, about 10, about 12, about 14, about 16,about 18, about 20 or about 24 hours. The maximum plasma concentrationof an active agent may be reached at a time following administrationfrom between about 0.1 hr to about 24 hr, or from about 0.25 hr to about10 hr, or from about 0.25 hr to about 8 hr, or from about 0.5 hr toabout 6 hr, or from about 0.5 hr to about 4 hr, or from about 0.5 hr toabout 2 hr, or from about 0.5 hr to about 1 hr. The time to maximumplasma concentration may be adjusted by adjusting various components ofthe controlled release carrier system as taught herein.

The plasma levels obtained may be adjusted by adjusting the dose of theactive agent, and/or by adjusting the components of the composition, anddesirable plasma levels will depend on the therapeutic range or itsindex for any particular active agent. It is readily within the skill ofone in the art to determine the desired therapeutic index.

The rate of active agent release from the composition may be varieddepending on the agent used and the dosage required. Release rates maybe different in different parts of the GI tract, and release rates maybe averaged over the time of transit through the GI tract (approximately8-24 hrs). Typical average release rates may vary substantially. Formany active agents, they may range from about 0.01 to about 500 mg/hr,e.g., from about 0.5 to about 250 mg/hr, from about 0.75 to about 100mg/hr, from about 1 to about 100 mg/hr, from about 2 to about 100 mg/hr,from about 5 to about 100 mg/hr, from about 10 to about 100 mg/hr, fromabout 10 to about 80 mg/hr, from about 20 to about 50 mg/hr, or fromabout 20 to about 40 mg/hr.

Dosage regimens for a particular active agent of interest may bedetermined by the physician in accordance with standard practices. Onceper day (QD) or twice per day (BID) dosing may be used to maintain asufficient clinical effect, e.g., to maintain pain relief.

Exemplary Non-Limiting Aspects of the Disclosure

The present disclosure includes a composition comprising: an opioid(e.g., about 2% by weight to about 50% by weight, relative to the totalweight of the composition, of an opioid selected from oxycodone,oxymorphone, hydrocodone, and hydromorphone, either in the free baseform or a pharmaceutically acceptable salt form thereof); sucroseacetate isobutyrate (SAIB); triacetin; isopropyl myristate (IPM);cellulose acetate butyrate (CAB), wherein the CAB has a number averagemolecular weight ranging from 66,000 Daltons to 83,000 Daltons, andwherein the CAB has at least one feature selected from a butyryl contentranging from about 17% to about 38%, an acetyl content ranging fromabout 13% to about 30%, and a hydroxyl content ranging from about 0.8%to about 1.7%; hydroxyethyl cellulose (HEC); and silicon dioxide,wherein the silicon dioxide is present in the composition in an amountfrom about 2.5% by weight to about 3.0% by weight relative to the totalweight of the composition. In some embodiments, the composition does notcomprise more than 5% water by weight, based on total weight of thecomposition. For instance, the composition may comprise water at fromabout 1.0 to about 2.5% by weight (e.g., from about 1.0 to about 2.0% byweight), based on total weight of the composition. In some embodiments,the composition is contained within a capsule (e.g., ahydroxymethylcellulose capsule).

Aspects, including embodiments, of the present subject matter describedabove may be beneficial alone or in combination, with one or more otheraspects or embodiments. Without limiting the foregoing description,certain non-limiting aspects of the disclosure numbered 1-604 areprovided below. As will be apparent to those of skill in the art uponreading this disclosure, each of the individually numbered aspects maybe used or combined with any of the preceding or following individuallynumbered aspects. This is intended to provide support for all suchcombinations of aspects and is not limited to combinations of aspectsexplicitly provided below.

-   1. A composition comprising:    -   a pharmacologically active agent;    -   about 35% by weight to about 45% by weight, based on total        weight of the composition, of a high viscosity liquid carrier        material (HVLCM) having a viscosity of at least 5000 cP at        37° C. that does not crystallize neat at 25° C. and 1        atmosphere;    -   about 31% by weight to about 45% by weight, based on total        weight of the composition, of a solvent;    -   about 2% by weight to about 10% by weight, based on total weight        of the composition, of a rheology modifier; and    -   a cellulose acetate butyrate.-   2. The composition of 1, wherein the HVLCM is sucrose acetate    isobutyrate (SAIB).-   3. The composition of 1 or 2, wherein the composition is in a    capsule having a water content of less than 10%.-   4. The composition of any one of 1 to 3, wherein the solvent is a    hydrophilic solvent.-   5. The composition of any one of 1 to 4, wherein the composition is    within a hydroxypropylmethylcellulose (HPMC) capsule.-   6. The composition of any one of 1 to 5, wherein the HVLCM is    sucrose acetate isobutyrate (SAIB), the solvent is triacetin, and    the rheology modifier is isopropyl myristate (IPM).-   7. The composition of any one of 1 to 6, comprising a mineral    particle.-   8. The composition of 7, wherein the mineral particle is selected    from talc, bentonite and kaolin.-   9. The composition of 7, wherein the mineral particle is selected    from silicon dioxide, zinc oxide, magnesium oxide, titanium oxide,    and calcium oxide.-   10. The composition of 7, wherein the mineral particle comprises    silicon dioxide.-   11. The composition of any one of 1 to 10, wherein the    pharmacologically active agent is selected from opioid, stimulant,    and depressant.-   12. The composition of 11, wherein the pharmacologically active    agent is an opioid.-   13. The composition of 11, wherein the pharmacologically active    agent is selected from oxycodone, oxymorphone, hydrocodone, and    hydromorphone, either in the free base form or a pharmaceutically    acceptable salt form thereof.-   14. The composition of 11, wherein the pharmacologically active    agent is oxycodone. 15. The composition of any one of 1 to 14,    comprising a surfactant.-   16. The composition of 15, wherein the surfactant is saturated    polyglycolized glyceride.-   17. The composition of any one of 1 to 16, wherein the composition    does not comprise more than 5% water by weight, based on total    weight of the composition.-   18. The composition of 17, wherein the composition does not comprise    more than 2.5% water by weight, based on total weight of the    composition.-   19. The composition of 17, wherein the composition does not comprise    more than 2.0% water by weight, based on total weight of the    composition.-   20. The composition of any one of 1 to 15, wherein the composition    comprises water at from about 1.0 to about 2.5% by weight, based on    total weight of the composition.-   21. The composition of 20, wherein the composition comprises water    at from about 1.0 to about 2.0% by weight, based on total weight of    the composition.-   22. The composition of 21, wherein the composition comprises water    at from about 1.0 to about 1.5% by weight, based on total weight of    the composition.-   23. A composition comprising:    -   a pharmacologically active agent;    -   about 35% by weight to about 45% by weight, based on total        weight of the composition, of sucrose acetate isobutyrate        (SAIB);    -   about 31% by weight to about 45% by weight, based on total        weight of the composition, of triacetin;    -   about 2% by weight to about 10% by weight, based on total weight        of the composition, of isopropyl myristate (IPM); and    -   about 4% to about 6% of a cellulose acetate butyrate (CAB),        based on total weight of the composition.-   24. The composition of 23, wherein the cellulose acetate butyrate    comprises CAB having a number average molecular weight ranging from    50,000 Daltons to 100,000 Daltons.-   25. The composition of 23 or 24, wherein the cellulose acetate    butyrate comprises CAB having at least one feature selected from a    butyryl content ranging from about 17% to about 41%, an acetyl    content ranging from about 13% to about 30%, and a hydroxyl content    ranging from about 0.5% to about 1.7%.-   26. A composition comprising:    -   a pharmacologically active agent;    -   at least 35% by weight of a high viscosity liquid carrier        material (HVLCM) having a viscosity of at least 5000 cP at        37° C. that does not crystallize neat at 25° C. and 1        atmosphere, based on the total weight of the composition;    -   a solvent;    -   about 2% by weight to about 10% by weight, based on total weight        of the composition, of a rheology modifier; and    -   a cellulose acetate butyrate (CAB), wherein the HVLCM and the        solvent are present in the composition at a ratio of about 1.3:1        to about 1:1.-   27. The composition of 26, wherein the HVLCM is sucrose acetate    isobutyrate (SAIB).-   28. The composition of 26 or 27, wherein the composition is in a    capsule having a water content of less than 10%.-   29. The composition of any one of 26 to 28, wherein the solvent is a    hydrophilic solvent.-   30. The composition of any one of 26 to 29, wherein the composition    is within a hydroxypropylmethylcellulose (HPMC) capsule.-   31. The composition of any one of 26 to 30, wherein the HVLCM is    sucrose acetate isobutyrate (SAIB), the solvent is triacetin, and    the rheology modifier is isopropyl myristate (IPM).-   32. The composition of any one of 26 to 31, comprising a mineral    particle.-   33. The composition of 32, wherein the mineral particle is selected    from talc, bentonite and kaolin.-   34. The composition of 32, wherein the mineral particle is selected    from silicon dioxide, zinc oxide, magnesium oxide, titanium oxide,    and calcium oxide.-   35. The composition of 32, wherein the mineral particle comprises    silicon dioxide.-   36. The composition of any one of 26 to 35, wherein the    pharmacologically active agent is selected from opioid, stimulant,    and depressant.-   37. The composition of 36, wherein the pharmacologically active    agent is an opioid.-   38. The composition of 36, wherein the pharmacologically active    agent is selected from oxycodone, oxymorphone, hydrocodone, and    hydromorphone, either in the free base form or a pharmaceutically    acceptable salt form thereof.-   39. The composition of 36, wherein the pharmacologically active    agent is oxycodone.-   40. The composition of any one of 26 to 39, comprising a surfactant.-   41. The composition of 40, wherein the surfactant is saturated    polyglycolized glyceride.-   42. The composition of any one of 26 to 41, wherein the composition    does not comprise more than 5% water by weight, based on total    weight of the composition.-   43. The composition of 42, wherein the composition does not comprise    more than 2.5% water by weight, based on total weight of the    composition.-   44. The composition of 42, wherein the composition does not comprise    more than 2.0% water by weight, based on total weight of the    composition.-   45. The composition of any one of 26 to 41, wherein the composition    comprises water at from about 1.0 to about 2.5% by weight, based on    total weight of the composition.-   46. The composition of 45, wherein the composition comprises water    at from about 1.0 to about 2.0% by weight, based on total weight of    the composition.-   47. The composition of 45, wherein the composition comprises water    at from about 1.0 to about 1.5% by weight, based on total weight of    the composition.-   48. A composition comprising:    -   a pharmacologically active agent;    -   at least 35% by weight of a high viscosity liquid carrier        material (HVLCM) having a viscosity of at least 5000 cP at        37° C. that does not crystallize neat at 25° C. and 1        atmosphere, based on the total weight of the composition;    -   a solvent;    -   a rheology modifier; and    -   a cellulose acetate butyrate (CAB), wherein the HVLCM, the        solvent and the rheology modifier are present in the composition        at a ratio of about 1.3:1.0:0.3 to about 1.0:1.0:0.05.-   49. The composition of 48, wherein the HVLCM is sucrose acetate    isobutyrate (SAIB).-   50. The composition of 48 or 49, wherein the composition is in a    capsule having a water content of less than 10%.-   51. The composition of any one of 48 to 50, wherein the solvent is a    hydrophilic solvent.-   52. The composition of any one of 48 to 51, wherein the composition    is within a hydroxypropylmethylcellulose (HPMC) capsule.-   53. The composition of any one of 48 to 52, wherein the HVLCM is    sucrose acetate isobutyrate (SAIB), the solvent is triacetin, and    the rheology modifier is isopropyl myristate (IPM).-   54. The composition of any one of 48 to 53, comprising a mineral    particle.-   55. The composition of 54, wherein the mineral particle is selected    from talc, bentonite and kaolin.-   56. The composition of 54, wherein the mineral particle is selected    from silicon dioxide, zinc oxide, magnesium oxide, titanium oxide,    and calcium oxide.-   57. The composition of 54, wherein the mineral particle comprises    silicon dioxide.-   58. The composition of any one of 48 to 57, wherein the    pharmacologically active agent is selected from opioid, stimulant,    and depressant.-   59. The composition of 58, wherein the pharmacologically active    agent is an opioid.-   60. The composition of 58, wherein the pharmacologically active    agent is selected from oxycodone, oxymorphone, hydrocodone, and    hydromorphone, either in the free base form or a pharmaceutically    acceptable salt form thereof.-   61. The composition of 58, wherein the pharmacologically active    agent is oxycodone.-   62. The composition of any one of 48 to 61, comprising a surfactant.-   63. The composition of 62, wherein the surfactant is saturated    polyglycolized glyceride.-   64. The composition of any one of 48 to 63, wherein the composition    does not comprise more than 5% water by weight, based on total    weight of the composition.-   65. The composition of 64, wherein the composition does not comprise    more than 2.5% water by weight, based on total weight of the    composition.-   66. The composition of 64, wherein the composition does not comprise    more than 2.0% water by weight, based on total weight of the    composition.-   67. The composition of any one of 48 to 63, wherein the composition    comprises water at from about 1.0 to about 2.5% by weight, based on    total weight of the composition.-   68. The composition of 67, wherein the composition comprises water    at from about 1.0 to about 2.0% by weight, based on total weight of    the composition.-   69. The composition of 68, wherein the composition comprises water    at from about 1.0 to about 1.5% by weight, based on total weight of    the composition.-   70. A composition comprising:    -   a pharmacologically active agent;    -   a high viscosity liquid carrier material (HVLCM) having a        viscosity of at least 5000 cP at 37° C. that does not        crystallize neat at 25° C. and 1 atmosphere;    -   a solvent;    -   a rheology modifier; and    -   a cellulose acetate butyrate (CAB), wherein the HVLCM, the        solvent and the rheology modifier are present in the composition        at a ratio sufficient to increase reproducibility of release        relative to Reference Formulation A when assayed in a USP        Apparatus 2 dissolution tester modified to have a 20-mesh basket        for containing the composition.-   71. The composition of 70, wherein the HVLCM is sucrose acetate    isobutyrate (SAIB).-   72. The composition of any one of 70 to 71, wherein the composition    is in a capsule having a water content of less than 10%.-   73. The composition of any one of 70 to 72, wherein the solvent is a    hydrophilic solvent.-   74. The composition of any one of 70 to 73, wherein the composition    is within a hydroxypropyl methylcellulose (HPMC) capsule.-   75. The composition of any one of 70 to 74, wherein the HVLCM is    sucrose acetate isobutyrate (SAIB), the solvent is triacetin, and    the rheology modifier is isopropyl myristate (IPM).-   76. The composition of any one of 70 to 75, comprising a mineral    particle.-   77. The composition of 76, wherein the mineral particle is selected    from talc, bentonite and kaolin.-   78. The composition of 76, wherein the mineral particle is selected    from silicon dioxide, zinc oxide, magnesium oxide, titanium oxide,    and calcium oxide.-   79. The composition of 76, wherein the mineral particle comprises    silicon dioxide.-   80. The composition of any one of 70 to 79, wherein the    pharmacologically active agent is selected from opioid, stimulant,    and depressant.-   81. The composition of 80, wherein the pharmacologically active    agent is an opioid.-   82. The composition of 80, wherein the pharmacologically active    agent is selected from oxycodone, oxymorphone, hydrocodone, and    hydromorphone, either in the free base form or a pharmaceutically    acceptable salt form thereof.-   83. The composition of 80, wherein the pharmacologically active    agent is oxycodone.-   84. The composition of any one of 70 to 83, comprising a surfactant.-   85. The composition of 84, wherein the surfactant is saturated    polyglycolized glyceride.-   86. The composition of any one of 70 to 85, wherein the composition    does not comprise more than 5% water by weight, based on total    weight of the composition.-   87. The composition of 86, wherein the composition does not comprise    more than 2.5% water by weight, based on total weight of the    composition.-   88. The composition of 86, wherein the composition does not comprise    more than 2.0% water by weight, based on total weight of the    composition.-   89. The composition of any one of 70 to 85, wherein the composition    comprises water at from about 1.0 to about 2.5% by weight, based on    total weight of the composition.-   90. The composition of 89, wherein the composition comprises water    at from about 1.0 to about 2.0% by weight, based on total weight of    the composition.-   91. The composition of 90, wherein the composition comprises water    at from about 1.0 to about 1.5% by weight, based on total weight of    the composition.-   92. A composition comprising:    -   a pharmacologically active agent;    -   a high viscosity liquid carrier material (HVLCM) having a        viscosity of at least 5000 cP at 37° C. that does not        crystallize neat at 25° C. and 1 atmosphere;    -   a solvent;    -   a rheology modifier; and    -   a cellulose acetate butyrate,    -   wherein the composition is encapsulated within a        hydroxypropylmethylcellulose capsule, and    -   wherein the composition within the capsule comprises less than        5% water by weight, based on total weight of the composition        within the capsule.-   93. The composition of 92, wherein the composition comprises less    than 2% water by weight, based on total weight of the composition.-   94. The composition of 92, wherein the HVLCM is sucrose acetate    isobutyrate (SAIB).-   95. The composition of any one of 92 to 94, wherein the solvent is a    hydrophilic solvent.-   96. The composition of any one of 92 to 95, wherein the HVLCM is    sucrose acetate isobutyrate (SAIB), the solvent is triacetin, and    the rheology modifier is isopropyl myristate (IPM).-   97. The composition of any one of 92 to 96, comprising a mineral    particle.-   98. The composition of 97, wherein the mineral particle is selected    from talc, bentonite and kaolin.-   99. The composition of 97, wherein the mineral particle is selected    from silicon dioxide, zinc oxide, magnesium oxide, titanium oxide,    and calcium oxide.-   100. The composition of 97, wherein the mineral particle comprises    silicon dioxide.-   101. The composition of any one of 92 to 100, wherein the    pharmacologically active agent is selected from opioid, stimulant,    and depressant.-   102. The composition of 101, wherein the pharmacologically active    agent is an opioid.-   103. The composition of 101, wherein the pharmacologically active    agent is selected from oxycodone, oxymorphone, hydrocodone, and    hydromorphone, either in the free base form or a pharmaceutically    acceptable salt form thereof.-   104. The composition of 101, wherein the pharmacologically active    agent is oxycodone.-   105. The composition of any one of 92 to 104, comprising a    surfactant.-   106. The composition of 105, wherein the surfactant is saturated    polyglycolized glyceride.-   107. A composition comprising:    -   a pharmacologically active agent; and    -   means for reducing a storage time-dependent change in an in        vitro release profile of a composition relative to Reference        Formulation A.-   108. The composition of 107, wherein the storage time-dependent    change in the release profile occurs following storage for 12 months    at 25° C. and 60% RH.-   109. The composition of 107, wherein Reference Formulation A    exhibits more than 10% mean drug release decline, a similarity    factor (f₂) of less than 50, when stored at 40° C./75% RH for a one    month period of time relative to its initial release profile.-   110. A composition comprising:    -   oxycodone at about 5% by weight to about 10% by weight relative        to the total weight of the composition; and    -   means for reducing a storage time-dependent change in an in        vitro release profile of the composition Relative to Ref.        Formulation A.-   111. The composition of 110, wherein the storage time-dependent    change in the release profile occurs following storage for 12 months    at 25° C. and 60% RH.-   112. The composition of 110, wherein Reference Formulation A    exhibits more than 10% mean drug release decline, a similarity    factor (f₂) of less than 50, when stored at 40° C./75% RH for a one    month period of time relative to its initial release profile.-   113. A method of orally administering a composition, comprising:    -   reducing a time-dependent change in an in vitro release profile        of a composition by formulating the composition to include, in        addition to a pharmacologically active agent,        -   about 35% by weight to about 45% by weight, based on total            weight of the composition, of a high viscosity liquid            carrier material (HVLCM) having a viscosity of at least 5000            cP at 37° C. that does not crystallize neat at 25° C. and 1            atmosphere,        -   about 31% by weight to about 45% by weight, based on total            weight of the composition, of a solvent,        -   about 2% by weight to about 10% by weight, based on total            weight of the composition, of a rheology modifier, and        -   a cellulose acetate butyrate; and    -   orally administering the composition.-   114. The method of 113, wherein the in vitro release profile results    remain similar, a similarity factor (f₂) of greater than 50, for the    composition when stored at 40 C/75% RH for a one month period of    time relative to an initial release profile.-   115. The method of 113, wherein the in vitro release profile results    remain similar, a similarity factor (f₂) of greater than 60, for the    composition when stored at 40 C/75% RH for a one month period of    time relative to an initial release profile.-   116. The method of 113, wherein the in vitro release profile results    remain similar, a similarity factor (f₂) of greater than 70, for the    composition when stored at 40 C/75% RH for a one month period of    time relative to an initial release profile.-   117. The method of 113, wherein the in vitro release profile results    remain similar, a similarity factor (f₂) of greater than 80, for the    composition when stored at 40 C/75% RH for a one month period of    time relative to an initial release profile.-   118. The method of 113, wherein the in vitro release profile results    remain similar, a similarity factor (f₂) of greater than 90, for the    composition when stored at 40 C/75% RH for a one month period of    time relative to an initial release profile.-   119. The method of 113, wherein the HVLCM is sucrose acetate    isobutyrate (SAIB).-   120. The method of 113 or 119, wherein the composition is in a    capsule having a water content of less than 10%.-   121. The method of any one of 113 to 120, wherein the solvent is a    hydrophilic solvent.-   122. The method of any one of 113 to 121, wherein the composition is    within a hydroxypropyl methylcellulose (HPMC) capsule.-   123. The method of any one of 113 to 122, wherein the HVLCM is    sucrose acetate isobutyrate (SAIB), the solvent is triacetin, and    the rheology modifier is isopropyl myristate (IPM).-   124. The method of any one of 113 to 123, wherein the composition    comprises a mineral particle.-   125. The method of 124, wherein the mineral particle is selected    from talc, bentonite and kaolin.-   126. The method of 124, wherein the mineral particle is selected    from silicon dioxide, zinc oxide, magnesium oxide, titanium oxide,    and calcium oxide.-   127. The method of 124, wherein the mineral particle comprises    silicon dioxide.-   128. The method of any one of 113 to 127, wherein the    pharmacologically active agent is selected from opioid, stimulant,    and depressant.-   129. The method of 128, wherein the pharmacologically active agent    is an opioid.-   130. The method of 128, wherein the pharmacologically active agent    is selected from oxycodone, oxymorphone, hydrocodone, and    hydromorphone, either in the free base form or a pharmaceutically    acceptable salt form thereof.-   131. The method of 128, wherein the pharmacologically active agent    is oxycodone.-   132. The method of any one of 113 to 131, wherein the composition    does not comprise more than 5% water by weight, based on total    weight of the composition.-   133. The method of 132, wherein the composition does not comprise    more than 2.5% water by weight, based on total weight of the    composition.-   134. The method of 132, wherein the composition does not comprise    more than 2.0% water by weight, based on total weight of the    composition.-   135. The method of any one of 113 to 131, wherein the composition    comprises water at from about 1.0 to about 2.5% by weight, based on    total weight of the composition.-   136. The method of 135, wherein the composition comprises water at    from about 1.0 to about 2.0% by weight, based on total weight of the    composition.-   137. The method of 136, wherein the composition comprises water at    from about 1.0 to about 1.5% by weight, based on total weight of the    composition.-   138. A method of reducing a time-dependent change in an in vitro    release profile of a pharmacologically active agent from a    composition, wherein the method comprises formulating the    pharmacologically active agent with (a) a high viscosity liquid    carrier material (HVLCM) having a viscosity of at least 5000 cP at    37° C. that does not crystallize neat at 25° C. and 1    atmosphere, (b) a solvent, (c) a rheology modifier and (d) cellulose    acetate butyrate, such that the composition comprises about 35% by    weight to about 45% by weight, based on total weight of the    composition, of the high viscosity liquid carrier material (HVLCM)    having a viscosity of at least 5000 cP at 37° C. that does not    crystallize neat at 25° C. and 1 atmosphere, about 31% by weight to    about 45% by weight, based on total weight of the composition, of    the solvent, about 2% by weight to about 10% by weight, based on    total weight of the composition, of the rheology modifier, and the    cellulose acetate butyrate.-   139. The method of 138, wherein the in vitro release profile results    remain similar, a similarity factor (f₂) of greater than 50, for the    composition when stored at 40 C/75% RH for a one month period of    time relative to an initial release profile.-   140. The method of 138, wherein the in vitro release profile results    remain similar, a similarity factor (f₂) of greater than 60, for the    composition when stored at 40 C/75% RH for a one month period of    time relative to an initial release profile.-   141. The method of 138, wherein the in vitro release profile results    remain similar, a similarity factor (f₂) of greater than 70, for the    composition when stored at 40 C/75% RH for a one month period of    time relative to an initial release profile.-   142. The method of 138, wherein the in vitro release profile results    remain similar, a similarity factor (f₂) of greater than 80, for the    composition when stored at 40 C/75% RH for a one month period of    time relative to an initial release profile.-   143. The method of 138, wherein the in vitro release profile results    remain similar, a similarity factor (f₂) of greater than 90, for the    composition when stored at 40 C/75% RH for a one month period of    time relative to an initial release profile.-   144. Use of (a) a high viscosity liquid carrier material (HVLCM)    having a viscosity of at least 5000 cP at 37 C that does not    crystallize neat at 25° C. and 1 atmosphere, (b) a solvent, (c) a    rheology modifier and (d) cellulose acetate butyrate, for reducing a    time-dependent change in an in vitro release profile of a    pharmacologically active agent from a composition, wherein the use    comprises formulating the pharmacologically active agent with (a)    the high viscosity liquid carrier material (HVLCM) having a    viscosity of at least 5000 cP at 37° C. that does not crystallize    neat at 25 C and 1 atmosphere, (b) the solvent, (c) the rheology    modifier and (d) cellulose acetate butyrate, thereby providing a    composition that comprises about 35% by weight to about 45% by    weight, based on total weight of the composition, of the high    viscosity liquid carrier material (HVLCM) having a viscosity of at    least 5000 cP at 37° C. that does not crystallize neat at 25° C. and    1 atmosphere, about 31% by weight to about 45% by weight, based on    total weight of the composition, of the solvent, about 2% by weight    to about 10% by weight, based on total weight of the composition, of    the rheology modifier, and the cellulose acetate butyrate.-   145. The use of 144, wherein the in vitro release profile results    remain similar, a similarity factor (f₂) of greater than 50, for the    composition when stored at 40 C/75% RH for a one month period of    time relative to an initial release profile.-   146. The use of 144, wherein the in vitro release profile results    remain similar, a similarity factor (f₂) of greater than 60, for the    composition when stored at 40 C/75% RH for a one month period of    time relative to an initial release profile.-   147. The use of 144, wherein the in vitro release profile results    remain similar, a similarity factor (f₂) of greater than 70, for the    composition when stored at 40 C/75% RH for a one month period of    time relative to an initial release profile.-   148. The use of 144, wherein the in vitro release profile results    remain similar, a similarity factor (f₂) of greater than 80, for the    composition when stored at 40 C/75% RH for a one month period of    time relative to an initial release profile.-   149. The use of 144, wherein the in vitro release profile results    remain similar, a similarity factor (f₂) of greater than 90, for the    composition when stored at 40 C/75% RH for a one month period of    time relative to an initial release profile.-   150. A method of orally administering a composition, comprising:    -   reducing a time-dependent change in an in vitro release profile        of a composition by formulating the composition to include, in        addition to a pharmacologically active agent,        -   at least 35% by weight of a high viscosity liquid carrier            material (HVLCM) having a viscosity of at least 5000 cP at            37° C. that does not crystallize neat at 25° C. and 1            atmosphere,        -   a solvent;        -   about 2% by weight to about 10% by weight, based on total            weight of the composition, of a rheology modifier, and        -   a cellulose acetate butyrate (CAB), wherein the HVLCM and            the solvent are present in the composition at a ratio of            about 1.3:1.0 to about 1.0:1.0; and    -   orally administering the composition.-   151. The method of 150, wherein the in vitro release profile results    remain similar, a similarity factor (f₂) of greater than 50, for the    composition when stored at 40 C/75% RH for a one month period of    time relative to an initial release profile.-   152. The method of 150, wherein the in vitro release profile results    remain similar, a similarity factor (f₂) of greater than 60, for the    composition when stored at 40 C/75% RH for a one month period of    time relative to an initial release profile.-   153. The method of 150, wherein the in vitro release profile results    remain similar, a similarity factor (f₂) of greater than 70, for the    composition when stored at 40 C/75% RH for a one month period of    time relative to an initial release profile.-   154. The method of 150, wherein the in vitro release profile results    remain similar, a similarity factor (f₂) of greater than 80, for the    composition when stored at 40 C/75% RH for a one month period of    time relative to an initial release profile.-   155. The method of 150, wherein the in vitro release profile results    remain similar, a similarity factor (f₂) of greater than 90, for the    composition when stored at 40 C/75% RH for a one month period of    time relative to an initial release profile.-   156. The method of any one of 150 to 155, wherein the HVLCM is    sucrose acetate isobutyrate (SAIB).-   157. The method of any one of 150 to 156, wherein the composition is    in a capsule having a water content of less than 10%.-   158. The method of any one of 150 to 157, wherein the solvent is a    hydrophilic solvent.-   159. The method of any one of 150 to 158, wherein the composition is    within a hydroxypropyl methylcellulose (HPMC) capsule.-   160. The method of any one of 150 to 159, wherein the HVLCM is    sucrose acetate isobutyrate (SAIB), the solvent is triacetin, and    the rheology modifier is isopropyl myristate (IPM).-   161. The method of any one of 150 to 160, wherein the composition    comprises a mineral particle.-   162. The method of 161, wherein the mineral particle is selected    from talc, bentonite and kaolin.-   163. The method of 161, wherein the mineral particle is selected    from silicon dioxide, zinc oxide, magnesium oxide, titanium oxide,    and calcium oxide.-   164. The method of 161, wherein the mineral particle comprises    silicon dioxide.-   165. The method of any one of 150 to 164, wherein the    pharmacologically active agent is selected from opioid, stimulant,    and depressant.-   166. The method of 165, wherein the pharmacologically active agent    is an opioid.-   167. The method of 165, wherein the pharmacologically active agent    is selected from oxycodone, oxymorphone, hydrocodone, and    hydromorphone, either in the free base form or a pharmaceutically    acceptable salt form thereof.-   168. The method of 165, wherein the pharmacologically active agent    is oxycodone.-   169. The method of any one of 150 to 168, wherein the composition    does not comprise more than 5% water by weight, based on total    weight of the composition.-   170. The method of 169, wherein the composition does not comprise    more than 2.5% water by weight, based on total weight of the    composition.-   171. The method of 169, wherein the composition does not comprise    more than 2.0% water by weight, based on total weight of the    composition.-   172. The method of any one of 150 to 168, wherein the composition    comprises water at from about 1.0 to about 2.5% by weight, based on    total weight of the composition.-   173. The method of 172, wherein the composition comprises water at    from about 1.0 to about 2.0% by weight, based on total weight of the    composition.-   174. The method of 173, wherein the composition comprises water at    from about 1.0 to about 1.5% by weight, based on total weight of the    composition.-   175. A method of orally administering a composition, comprising:    -   reducing a time-dependent change in an in vitro release profile        of a composition by formulating the composition to include, in        addition to a pharmacologically active agent,        -   at least 35% by weight of a high viscosity liquid carrier            material (HVLCM) having a viscosity of at least 5000 cP at            37° C. that does not crystallize neat at 25° C. and 1            atmosphere;        -   a solvent;        -   a rheology modifier; and        -   a cellulose acetate butyrate (CAB), wherein the HVLCM, the            solvent and the rheology modifier are present in the            composition at a ratio of about 1.3:1.0:0.3 to about            1.0:1.0:0.05; and    -   orally administering the composition.-   176. The method of 175, wherein the in vitro release profile results    remain similar, a similarity factor (f₂) of greater than 50, for the    composition when stored at 40 C/75% RH for a one month period of    time relative to an initial release profile.-   177. The method of 175, wherein the in vitro release profile results    remain similar, a similarity factor (f₂) of greater than 60, for the    composition when stored at 40 C/75% RH for a one month period of    time relative to an initial release profile.-   178. The method of 175, wherein the in vitro release profile results    remain similar, a similarity factor (f₂) of greater than 70, for the    composition when stored at 40 C/75% RH for a one month period of    time relative to an initial release profile.-   179. The method of 175, wherein the in vitro release profile results    remain similar, a similarity factor (f₂) of greater than 80, for the    composition when stored at 40 C/75% RH for a one month period of    time relative to an initial release profile.-   180. The method of 175, wherein the in vitro release profile results    remain similar, a similarity factor (f₂) of greater than 90, for the    composition when stored at 40 C/75% RH for a one month period of    time relative to an initial release profile.-   181. The method of any one of 175 to 180, wherein the HVLCM is    sucrose acetate isobutyrate (SAIB).-   182. The method of any one of 175 to 181, wherein the composition is    in a capsule having a water content of less than 10%.-   183. The method of any one of 175 to 182, wherein the solvent is a    hydrophilic solvent.-   184. The method of any one of 175 to 183, wherein the composition is    within a hydroxypropyl methylcellulose (HPMC) capsule.-   185. The method of any one of 175 to 184, wherein the HVLCM is    sucrose acetate isobutyrate (SAIB), the solvent is triacetin, and    the rheology modifier is isopropyl myristate (IPM).-   186. The method of any one of 175 to 185, wherein the composition    comprises a mineral particle.-   187. The method of 186, wherein the mineral particle is selected    from talc, bentonite and kaolin.-   188. The method of 186, wherein the mineral particle is selected    from silicon dioxide, zinc oxide, magnesium oxide, titanium oxide,    and calcium oxide.-   189. The method of 186, wherein the mineral particle comprises    silicon dioxide.-   190. The method of any one of 175 to 189, wherein the    pharmacologically active agent is selected from opioid, stimulant,    and depressant.-   191. The method of 190, wherein the pharmacologically active agent    is an opioid.-   192. The method of 190, wherein the pharmacologically active agent    is selected from oxycodone, oxymorphone, hydrocodone, and    hydromorphone, either in the free base form or a pharmaceutically    acceptable salt form thereof.-   193. The method of 190, wherein the pharmacologically active agent    is oxycodone.-   194. The method of any one of 175 to 193, wherein the composition    does not comprise more than 5% water by weight, based on total    weight of the composition.-   195. The method of 194, wherein the composition does not comprise    more than 2.5% water by weight, based on total weight of the    composition.-   196. The method of 194, wherein the composition does not comprise    more than 2.0% water by weight, based on total weight of the    composition.-   197. The method of any one of 175 to 193, wherein the composition    comprises water at from about 1.0 to about 2.5% by weight, based on    total weight of the composition.-   198. The method of 197, wherein the composition comprises water at    from about 1.0 to about 2.0% by weight, based on total weight of the    composition.-   199. The method of 198, wherein the composition comprises water at    from about 1.0 to about 1.5% by weight, based on total weight of the    composition.-   200. A method of orally administering a composition, comprising:    -   reducing a time-dependent change in an in vitro release profile        of a composition by formulating the composition to include, in        addition to a pharmacologically active agent,        -   a high viscosity liquid carrier material (HVLCM) having a            viscosity of at least 5000 cP at 37° C. that does not            crystallize neat at 25° C. and 1 atmosphere;        -   a solvent;        -   a rheology modifier; and        -   a cellulose acetate butyrate (CAB), wherein the HVLCM, the            solvent and the rheology modifier are present in the            composition at a ratio sufficient to increase            reproducibility of release relative to Reference Formulation            A when assayed in a USP Apparatus 2 dissolution tester            modified to have a 20-mesh basket for containing the            composition; and    -   orally administering the composition.-   201. The method of 200, wherein the in vitro release profile results    remain similar, a similarity factor (f₂) of greater than 50, for the    composition when stored at 40 C/75% RH for a one month period of    time relative to an initial release profile.-   202. The method of 200, wherein the in vitro release profile results    remain similar, a similarity factor (f₂) of greater than 60, for the    composition when stored at 40 C/75% RH for a one month period of    time relative to an initial release profile.-   203. The method of 200, wherein the in vitro release profile results    remain similar, a similarity factor (f₂) of greater than 70, for the    composition when stored at 40 C/75% RH for a one month period of    time relative to an initial release profile.-   204. The method of 200, wherein the in vitro release profile results    remain similar, a similarity factor (f₂) of greater than 80, for the    composition when stored at 40 C/75% RH for a one month period of    time relative to an initial release profile.-   205. The method of 200, wherein the in vitro release profile results    remain similar, a similarity factor (f₂) of greater than 90, for the    composition when stored at 40 C/75% RH for a one month period of    time relative to an initial release profile.-   206. The method of any one of 200 to 205, wherein the HVLCM is    sucrose acetate isobutyrate (SAIB).-   207. The method of any one of 200 to 206, wherein the composition is    in a capsule having a water content of less than 10%.-   208. The method of any one of 200 to 207, wherein the solvent is a    hydrophilic solvent.-   209. The method of any one of 200 to 208, wherein the composition is    within a hydroxypropyl methylcellulose (HPMC) capsule.-   210. The method of any one of 200 to 209, wherein the HVLCM is    sucrose acetate isobutyrate (SAIB), the solvent is triacetin, and    the rheology modifier is isopropyl myristate (IPM).-   211. The method of any one of 200 to 210, wherein the composition    comprises a mineral particle.-   212. The method of 211, wherein the mineral particle is selected    from talc, bentonite and kaolin.-   213. The method of 211, wherein the mineral particle is selected    from silicon dioxide, zinc oxide, magnesium oxide, titanium oxide,    and calcium oxide.-   214. The method of 211, wherein the mineral particle comprises    silicon dioxide.-   215. The method of any one of 200 to 214, wherein the    pharmacologically active agent is selected from opioid, stimulant,    and depressant.-   216. The method of 215, wherein the pharmacologically active agent    is an opioid.-   217. The method of 200, wherein the pharmacologically active agent    is selected from oxycodone, oxymorphone, hydrocodone, and    hydromorphone, either in the free base form or a pharmaceutically    acceptable salt form thereof.-   218. The method of 200, wherein the pharmacologically active agent    is oxycodone.-   219. The method of any one of 200 to 218, wherein the composition    does not comprise more than 5% water by weight, based on total    weight of the composition.-   220. The method of 219, wherein the composition does not comprise    more than 2.5% water by weight, based on total weight of the    composition.-   221. The method of 219, wherein the composition does not comprise    more than 2.0% water by weight, based on total weight of the    composition.-   222. The method of any one of 200 to 218, wherein the composition    comprises water at from about 1.0 to about 2.5% by weight, based on    total weight of the composition.-   223. The method of 222, wherein the composition comprises water at    from about 1.0 to about 2.0% by weight, based on total weight of the    composition.-   224. The method of 223, wherein the composition comprises water at    from about 1.0 to about 1.5% by weight, based on total weight of the    composition.-   225. A method of orally administering a composition, comprising:    -   reducing a storage time-dependent change in a release profile of        a composition by formulating the composition to include, in        addition to a pharmacologically active agent, means for the        reducing a storage time-dependent change in a release profile of        the composition relative to Reference Formulation A.-   226. The method of 225, wherein the storage time-dependent change in    the release profile occurs following storage for 12 months at 25° C.    and 60% RH.-   227. The method of 225, wherein Reference Formulation A exhibits    more than 10% mean drug release decline, a similarity factor (f₂) of    less than 50, when stored at 40° C./75% RH for a one month period of    time relative to its initial release profile.-   228. A composition comprising:    -   a pharmacologically active agent;    -   a high viscosity liquid carrier material (HVLCM) having a        viscosity of at least 5000 cP at 37° C. that does not        crystallize neat at 25° C. and 1 atmosphere;    -   a solvent;    -   a network former; and    -   a mineral particle, wherein the mineral particle is present in        the composition in an amount from about 2.4% by weight to about        5.4% by weight relative to the total weight of the composition.-   229. The composition of 228, wherein the mineral particle is    selected from talc, bentonite and kaolin.-   230. The composition of 228, wherein the mineral particle is    selected from silicon dioxide, zinc oxide, magnesium oxide, titanium    oxide, and calcium oxide.-   231. The composition of 228, wherein the mineral particle comprises    silicon dioxide.-   232. The composition of 228, wherein the pharmacologically active    agent is selected from opioid, stimulant, and depressant.-   233. The composition of 228, wherein the pharmacologically active    agent is an opioid.-   234. The composition of 228, wherein the pharmacologically active    agent is selected from oxycodone, oxymorphone, hydrocodone, and    hydromorphone, either in the free base form or a pharmaceutically    acceptable salt form thereof.-   235. The composition of 228, wherein the pharmacologically active    agent is oxycodone.-   236. The composition of any one of 228 to 235, wherein the HVLCM is    sucrose acetate isobutyrate (SAIB).-   237. The composition of any one of 228 to 236, comprising about 35%    by weight to about 45% by weight of the HVLCM relative to the total    weight of the composition.-   238. The composition of any one of 228 to 237, wherein the solvent    is selected from triacetin, N-methyl-2-pyrrolidone, 2-pyrrolidone,    dimethylsulfoxide, ethyl lactate, propylene carbonate and    glycofurol.-   239. The composition of any one of 228 to 238, wherein the solvent    comprises triacetin.-   240. The composition of any one of 228 to 238, wherein the solvent    comprises N-methyl-2-pyrrolidone.-   241. The composition of any one of 228 to 238, wherein the solvent    comprises 2-pyrrolidone.-   242. The composition of any one of 228 to 238, wherein the solvent    comprises dimethylsulfoxide.-   243. The composition of any one of 228 to 238, wherein the solvent    comprises ethyl lactate.-   244. The composition of any one of 228 to 238, wherein the solvent    comprises propylene carbonate.-   245. The composition of any one of 228 to 238, wherein the solvent    comprises glycofurol.-   246. The composition of any one of 228 to 245, comprising about 31%    by weight to about 45% by weight of the solvent relative to the    total weight of the composition.-   247. The composition of 246, comprising about 38% by weight to about    41% by weight of the solvent relative to the total weight of the    composition.-   248. The composition of any one of 228 to 247, further comprising a    rheology modifier.-   249. The composition of 248, wherein the rheology modifier is    selected from isopropyl myristate (IPM), caprylic/capric    triglyceride, ethyl oleate, triethyl citrate, dimethyl phthalate and    benzyl benzoate.-   250. The composition of 248, wherein the rheology modifier is IPM.-   251. The composition of 248, wherein the rheology modifier is    caprylic/capric triglyceride.-   252. The composition of 248, wherein the rheology modifier is ethyl    oleate.-   253. The composition of 248, wherein the rheology modifier is    triethyl citrate.-   254. The composition of 248, wherein the rheology modifier is    dimethyl phthalate.-   255. The composition of 248, wherein the rheology modifier is benzyl    benzoate.-   256. The composition of any one of 248 to 255, comprising about 2%    by weight to about 10% by weight of the rheology modifier relative    to the total weight of the composition.-   257. The composition of any one of 228 to 256, wherein the network    former is selected from cellulose acetate butyrate (CAB), cellulose    acetate phthalate, ethyl cellulose, hydroxypropylmethyl cellulose    and cellulose triacetate.-   258. The composition of any one of 228 to 257, wherein the network    former comprises cellulose acetate butyrate (CAB).-   259. The composition of any one of 228 to 258, wherein the network    former comprises CAB having a number average molecular weight    ranging from 50,000 Daltons to 100,000 Daltons.-   260. The composition of any one of 228 to 259, wherein the network    former comprises CAB having at least one feature selected from a    butyryl content ranging from about 17% to about 41%, an acetyl    content ranging from about 13% to about 30%, and a hydroxyl content    ranging from about 0.5% to about 1.7%.-   261. The composition of any one of 228 to 260, further comprising a    hydrophilic agent.-   262. The composition of 261, wherein the hydrophilic agent is    selected from hydroxyethyl cellulose (HEC), hydroxypropyl cellulose,    caboxymethyl cellulose, polyethylene glycol and    polyvinylpyrrolidone.-   263. The composition of 261, wherein the hydrophilic agent comprises    HEC.-   264. The composition of any one of 228 to 263, wherein the mineral    particle is present in the composition in an amount from about 2.5%    by weight to about 4.0% by weight relative to the total weight of    the composition.-   265. The composition of any one of 228 to 264, wherein the mineral    particle is present in the composition in an amount from about 2.5%    by weight to about 3.5% by weight relative to the total weight of    the composition.-   266. The composition of any one of 228 to 265, wherein the mineral    particle is present in the composition in an amount from about 2.5%    by weight to about 3.2% by weight relative to the total weight of    the composition.-   267. The composition of any one of 228 to 266, wherein the mineral    particle is present in the composition in an amount from about 2.5%    by weight to about 3.0% by weight relative to the total weight of    the composition.-   268. The composition of any one of 228 to 267, wherein the mineral    particle is present in the composition at from about 2.5% by weight    to about 2.9% by weight relative to the total weight of the    composition.-   269. The composition of any one of 228 to 268, wherein the    composition has a complex viscosity of from about 100 Pa·s to about    300 Pa·s, wherein the complex viscosity is determined at a constant    strain of 0.5%, a frequency of 1 Hz and a temperature of 25° C.-   270. The composition of any one of 228 to 269, wherein the    composition has a complex viscosity of from about 120 Pa·s to about    250 Pa·s, wherein the complex viscosity is determined at a constant    strain of 0.5%, a frequency of 1 Hz and a temperature of 25° C.-   271. The composition of any one of 228 to 270, wherein the    composition has a complex viscosity of from about 140 Pa·s to about    200 Pa·s, wherein the complex viscosity is determined at a constant    strain of 0.5%, a frequency of 1 Hz and a temperature of 25° C.-   272. The composition of any one of 228 to 271, wherein the ratio of    the HVLCM to the solvent in the composition is about 0.6:1 to 1.6:1.-   273. The composition of 272, wherein the ratio of the HVLCM to the    solvent in the composition is about 0.8:1 to 1.5:1.-   274. The composition of 273, wherein the ratio of the HVLCM to the    solvent in the composition is about 0.9:1 to 1.5:1.-   275. The composition of any one of 228 to 272, wherein the    composition comprises:    -   about 35% by weight to about 45% by weight of the HVLCM relative        to the total weight of the composition,    -   about 31% by weight to about 45% by weight of the solvent        relative to the total weight of the composition, and    -   about 2% by weight to about 10% by weight of the network former        relative to the total weight of the composition.-   276. The composition of 275, comprising about 0.1% by weight to    about 8% by weight of a rheology modifier relative to the total    weight of the composition.-   277. The composition of 275 to 276, comprising about 2% by weight to    about 10% by weight of a hydrophilic agent.-   278. The composition of any one of 228 to 277, wherein the    composition comprises:    -   about 39% by weight to about 41% by weight of the HVLCM relative        to the total weight of the composition,    -   about 38% by weight to about 40% by weight of the solvent        relative to the total weight of the composition, and    -   about 4% by weight to about 6% by weight of the network former        relative to the total weight of the composition.-   279. The composition of any one of 228 to 278, comprising about 2%    by weight to about 3% by weight of a rheology modifier relative to    the total weight of the composition.-   280. The composition of any one of 228 to 279, comprising about 5%    by weight to about 6% by weight of a hydrophilic agent relative to    the total weight of the composition.-   281. The composition of any one of 228 to 280, wherein the HVLCM is    SAIB, the solvent is triacetin, and the network former is CAB.-   282. The composition of 281, comprising IPM.-   283. The composition of 281 or 282, comprising HEC.-   284. The composition of any one of 228 to 283, wherein the    pharmacologically active agent is present in the composition at    about 2% by weight to about 50% by weight relative to the total    weight of the composition.-   285. The composition of any one of 228 to 284, wherein the    composition is contained within a capsule.-   286. The composition of any one of 228 to 285, wherein the    composition is contained within a capsule comprising hydroxypropyl    methylcellulose.-   287. The composition of any one of 228 to 286, wherein the    composition is contained within a hard capsule comprising    hydroxypropyl methylcellulose.-   288. The composition of any one of 228 to 287, comprising a    surfactant.-   289. The composition of 288, wherein the surfactant is saturated    polyglycolized glyceride.-   290. The composition of any one of 228 to 289, wherein the    composition does not comprise more than 5% water by weight, based on    total weight of the composition.-   291. The composition of 290, wherein the composition does not    comprise more than 2.5% water by weight, based on total weight of    the composition.-   292. The composition of 290, wherein the composition does not    comprise more than 2.0% water by weight, based on total weight of    the composition.-   293. The composition of any one of 228 to 289, wherein the    composition comprises water at from about 1.0 to about 2.5% by    weight, based on total weight of the composition.-   294. The composition of 293, wherein the composition comprises water    at from about 1.0 to about 2.0% by weight, based on total weight of    the composition.-   295. The composition of 294, wherein the composition comprises water    at from about 1.0 to about 1.5% by weight, based on total weight of    the composition.-   296. A composition comprising:    -   an opioid;    -   sucrose acetate isobutyrate (SAIB);    -   triacetin;    -   isopropyl myristate (IPM);    -   cellulose acetate butyrate (CAB);    -   hydroxyethyl cellulose (HEC); and    -   silicon dioxide, wherein the silicon dioxide is present in the        composition in an amount from about 2.4% by weight to about 5.4%        by weight relative to the total weight of the composition.-   297. The composition of 296, wherein the SAIB is present in the    composition in an amount from about 35% by weight to about 45% by    weight relative to the total weight of the composition, the    triacetin is present in the composition in an amount from about 31%    by weight to about 45% by weight relative to the total weight of the    composition, the IPM is present in the composition in an amount from    about 2% by weight to about 10% by weight relative to the total    weight of the composition, the CAB is present in the composition at    about 4% to about 6% by weight relative to the total weight of the    composition, and the HEC is present in the composition in an amount    from about 5% by weight to about 6% by weight relative to the total    weight of the composition.-   298. The composition of 296 or 297, comprising about 38% by weight    to about 41% by weight of the triacetin relative to the total weight    of the composition.-   299. The composition of any one of 296 to 298, comprising about 2%    by weight to about 3% by weight of the IPM relative to the total    weight of the composition.-   300. The composition of any one of 296 to 299, wherein the CAB has a    number average molecular weight ranging from 66,000 Daltons to    83,000 Daltons.-   301. The composition of any one of 296 to 300, wherein the CAB has    at least one feature selected from a butyryl content ranging from    about 17% to about 38%, an acetyl content ranging from about 13% to    about 30%, and a hydroxyl content ranging from about 0.8% to about    1.7%.-   302. The composition of any one of 296 to 301, wherein the silicon    dioxide is present in the composition in an amount from about 2.5%    by weight to about 3.5% by weight relative to the total weight of    the composition.-   303. The composition of any one of 296 to 302, wherein the silicon    dioxide is present in the composition in an amount from about 2.5%    by weight to about 3.2% by weight relative to the total weight of    the composition.-   304. The composition of any one of 296 to 303, wherein the silicon    dioxide is present in the composition in an amount from about 2.5%    by weight to about 3.0% by weight relative to the total weight of    the composition.-   305. The composition of any one of 296 to 304, wherein the silicon    dioxide is present in the composition in an amount from about 2.5%    by weight to about 2.9% by weight relative to the total weight of    the composition.-   306. The composition of any one of 296 to 305, wherein the    composition has a complex viscosity of from about 100 Pa·s to about    300 Pa·s, wherein the complex viscosity is determined at a constant    strain of 0.5% and a frequency of 1 Hz and a temperature of 25° C.-   307. The composition of any one of 296 to 306, wherein the    composition has a complex viscosity of from about 120 Pa·s to about    250 Pa·s, wherein the complex viscosity is determined at a constant    strain of 0.5% and a frequency of 1 Hz and a temperature of 25° C.-   308. The composition of any one of 296 to 307, wherein the    composition has a complex viscosity of from about 140 Pa·s to about    200 Pa·s, wherein the complex viscosity is determined at a constant    strain of 0.5% and a frequency of 1 Hz and a temperature of 25° C.-   309. The composition of any one of 296 to 308, wherein the opioid is    selected from oxycodone, oxymorphone, hydrocodone, and    hydromorphone, either in the free base form or a pharmaceutically    acceptable salt form thereof.-   310. The composition of any one of 296 to 309, wherein the opioid is    oxycodone.-   311. The composition of any one of 296 to 310, wherein the opioid is    present in the composition at about 5% by weight relative to the    total weight of the composition.-   312. The composition of any one of 296 to 311, wherein the    composition does not comprise more than 5% water by weight, based on    total weight of the composition.-   313. The composition of 312, wherein the composition does not    comprise more than 2.5% water by weight, based on total weight of    the composition.-   314. The composition of 312, wherein the composition does not    comprise more than 2.0% water by weight, based on total weight of    the composition.-   315. The composition of any one of 296 to 311, wherein the    composition comprises water at from about 1.0 to about 2.5% by    weight, based on total weight of the composition.-   316. The composition of 315, wherein the composition comprises water    at from about 1.0 to about 2.0% by weight, based on total weight of    the composition.-   317. The composition of 316, wherein the composition comprises water    at from about 1.0 to about 1.5% by weight, based on total weight of    the composition.-   318. A composition comprising:    -   oxycodone;    -   about 35% by weight to about 45% sucrose acetate isobutyrate        (SAIB) relative to the total weight of the composition;    -   about 31% by weight to about 45% of triacetin relative to the        total weight of the composition;    -   about 2% by weight to about 10% by weight of isopropyl myristate        (IPM) relative to the total weight of the composition;    -   about 4% to about 6% by weight of cellulose acetate butyrate        (CAB) relative to the total weight of the composition;    -   about 5% by weight to about 6% by weight of hydroxyethyl        cellulose (HEC) relative to the total weight of the composition;        and    -   about 2.4% by weight to about 5.4% by weight of silicon dioxide        relative to the total weight of the composition.-   319. A composition comprising:    -   oxycodone;    -   about 39% by weight to about 41% sucrose acetate isobutyrate        (SAIB) relative to the total weight of the composition;    -   about 38% by weight to about 41% of triacetin relative to the        total weight of the composition;    -   about 2% by weight to about 3% by weight of isopropyl myristate        (IPM) relative to the total weight of the composition;    -   about 4% to about 6% by weight of cellulose acetate butyrate        (CAB) relative to the total weight of the composition;    -   about 5% by weight to about 6% by weight of hydroxyethyl        cellulose (HEC) relative to the total weight of the composition;        and    -   about 2.5% by weight to about 3.2% by weight of silicon dioxide        relative to the total weight of the composition.-   320. A composition comprising:    -   about 5% by weight of oxycodone relative to the total weight of        the composition;    -   about 39% by weight to about 41% sucrose acetate isobutyrate        (SAIB) relative to the total weight of the composition;    -   about 38% by weight to about 41% of triacetin relative to the        total weight of the composition;    -   about 2% by weight to about 3% by weight of isopropyl myristate        (IPM) relative to the total weight of the composition;    -   about 4% to about 6% by weight of cellulose acetate butyrate        (CAB) relative to the total weight of the composition;    -   about 5% by weight to about 6% by weight of hydroxyethyl        cellulose (HEC) relative to the total weight of the composition;        and    -   about 2.5% by weight to about 3.2% by weight of silicon dioxide        relative to the total weight of the composition.-   321. A composition comprising:    -   oxycodone at about 5% by weight relative to the total weight of        the composition;    -   sucrose acetate isobutyrate (SAIB) at about 40% by weight        relative to the total weight of the composition;    -   triacetin at about 39% by weight relative to the total weight of        the composition;    -   isopropyl myristate (IPM) at about 2.5% by weight relative to        the total weight of the composition;    -   cellulose acetate butyrate (CAB) at about 4.5% by weight        relative to the total weight of the composition;    -   hydroxyethyl cellulose (HEC) at about 5.5% by weight relative to        the total weight of the composition; and    -   silicon dioxide at about 2.9% by weight relative to the total        weight of the composition.-   322. A composition comprising:    -   oxycodone at about 5% by weight relative to the total weight of        the composition;    -   sucrose acetate isobutyrate (SAIB) at about 40% by weight        relative to the total weight of the composition;    -   triacetin at about 39% by weight relative to the total weight of        the composition;    -   isopropyl myristate (IPM) at about 2.5% by weight relative to        the total weight of the composition;    -   cellulose acetate butyrate (CAB) at about 4.5% by weight        relative to the total weight of the composition;    -   hydroxyethyl cellulose (HEC) at about 5.5% by weight relative to        the total weight of the composition; and    -   silicon dioxide at about 2.9% by weight relative to the total        weight of the composition, wherein the composition is        encapsulated in a hydroxypropylmethylcellulose (HPMC) capsule.-   323. A composition comprising:    -   a pharmacologically active agent;    -   a high viscosity liquid carrier material (HVLCM) having a        viscosity of at least 5000 cP at 37° C. that does not        crystallize neat at 25° C. and 1 atmosphere;    -   a solvent;    -   a network former; and    -   a mineral particle, wherein the HVLCM, the solvent, the network        former, and the mineral particle are present in a ratio        sufficient to reduce a storage time-dependent change in an in        vitro release profile of a composition relative to Reference        Formulation A.-   324. The composition of 323, wherein Reference Formulation A    exhibits more than 10% mean drug release decline, a similarity    factor (f₂) of less than 50, when stored at 40° C./75% RH for a one    month period of time relative to its initial release profile.-   325. The composition of 323, wherein the mineral particle is    selected from talc, bentonite and kaolin.-   326. The composition of 323, wherein the mineral particle is    selected from silicon dioxide, zinc oxide, magnesium oxide, titanium    oxide, and calcium oxide.-   327. The composition of 323, wherein the mineral particle comprises    silicon dioxide.-   328. The composition of 323, wherein the pharmacologically active    agent is selected from opioid, stimulant, and depressant.-   329. The composition of 323, wherein the pharmacologically active    agent is an opioid.-   330. The composition of 323, wherein the pharmacologically active    agent is selected from oxycodone, oxymorphone, hydrocodone, and    hydromorphone, either in the free base form or a pharmaceutically    acceptable salt form thereof.-   331. The composition of 323, wherein the pharmacologically active    agent is oxycodone.-   332. The composition of any one of 323 to 331, wherein the HVLCM is    sucrose acetate isobutyrate (SAIB).-   333. The composition of any one of 323 to 332, comprising about 35%    by weight to about 45% by weight of the HVLCM relative to the total    weight of the composition.-   334. The composition of any one of 323 to 333, wherein the solvent    is selected from triacetin, N-methyl-2-pyrrolidone, 2-pyrrolidone,    dimethylsulfoxide, ethyl lactate, propylene carbonate and    glycofurol.-   335. The composition of any one of 323 to 334, wherein the solvent    comprises triacetin.-   336. The composition of any one of 323 to 334, wherein the solvent    comprises N-methyl-2-pyrrolidone.-   337. The composition of any one of 323 to 334, wherein the solvent    comprises 2-pyrrolidone.-   338. The composition of any one of 323 to 334, wherein the solvent    comprises dimethylsulfoxide.-   339. The composition of any one of 323 to 334, wherein the solvent    comprises ethyl lactate.-   340. The composition of any one of 323 to 334, wherein the solvent    comprises propylene carbonate.-   341. The composition of any one of 323 to 334, wherein the solvent    comprises glycofurol.-   342. The composition of any one of 323 to 341, comprising about 31%    by weight to about 45% by weight of the solvent relative to the    total weight of the composition.-   343. The composition of 342, comprising about 38% by weight to about    41% by weight of the solvent relative to the total weight of the    composition.-   344. The composition of any one of 323 to 343, further comprising a    rheology modifier.-   345. The composition of 344, wherein the rheology modifier is    selected from isopropyl myristate (IPM), caprylic/capric    triglyceride, ethyl oleate, triethyl citrate, dimethyl phthalate and    benzyl benzoate.-   346. The composition of 344, wherein the rheology modifier is IPM.-   347. The composition of 344, wherein the rheology modifier is    caprylic/capric triglyceride.-   348. The composition of 344, wherein the rheology modifier is ethyl    oleate.-   349. The composition of 344, wherein the rheology modifier is    triethyl citrate.-   350. The composition of 344, wherein the rheology modifier is    dimethyl phthalate.-   351. The composition of 344, wherein the rheology modifier is benzyl    benzoate.-   352. The composition of any one of 344-351, comprising about 2% by    weight to about 10% by weight of the rheology modifier relative to    the total weight of the composition.-   353. The composition of any one of 323 to 351, wherein the network    former is selected from cellulose acetate butyrate (CAB), cellulose    acetate phthalate, ethyl cellulose, hydroxypropyl methylcellulose    and cellulose triacetate.-   354. The composition of any one of 323 to 353, wherein the network    former comprises cellulose acetate butyrate (CAB).-   355. The composition of any one of 323 to 354, wherein the network    former comprises CAB having a number average molecular weight    ranging from 50,000 Daltons to 100,000 Daltons.-   356. The composition of any one of 323 to 355, wherein the network    former comprises CAB having at least one feature selected from a    butyryl content ranging from about 17% to about 41%, an acetyl    content ranging from about 13% to about 30%, and a hydroxyl content    ranging from about 0.5% to about 1.7%.-   357. The composition of any one of 323 to 356, further comprising a    hydrophilic agent.-   358. The composition of 357, wherein the hydrophilic agent is    selected from hydroxyethyl cellulose (HEC), hydroxypropyl cellulose,    caboxymethyl cellulose, polyethylene glycol and    polyvinylpyrrolidone.-   359. The composition of 357, wherein the hydrophilic agent comprises    HEC.-   360. The composition of any one of 323 to 359, wherein the mineral    particle is present in the composition in an amount from about 2.5%    by weight to about 4.0% by weight relative to the total weight of    the composition.-   361. The composition of any one of 323 to 360, wherein the mineral    particle is present in the composition in an amount from about 2.5%    by weight to about 3.5% by weight relative to the total weight of    the composition.-   362. The composition of any one of 323 to 361, wherein the mineral    particle is present in the composition in an amount from about 2.5%    by weight to about 3.2% by weight relative to the total weight of    the composition.-   363. The composition of any one of 323 to 362, wherein the mineral    particle is present in the composition in an amount from about 2.5%    by weight to about 3.0% by weight relative to the total weight of    the composition.-   364. The composition of any one of 323 to 363, wherein the mineral    particle is present in the composition at from about 2.5% by weight    to about 2.9% by weight relative to the total weight of the    composition.-   365. The composition of any one of 323 to 364, wherein the    composition has a complex viscosity of from about 100 Pa·s to about    300 Pa·s, wherein the complex viscosity is determined at a constant    strain of 0.5% and a frequency of 1 Hz and a temperature of 25° C.-   366. The composition of any one of 323 to 365, wherein the    composition has a complex viscosity of from about 120 Pa·s to about    250 Pa·s, wherein the complex viscosity is determined at a constant    strain of 0.5% and a frequency of 1 Hz and a temperature of 25° C.-   367. The composition of any one of 323 to 366, wherein the    composition has a complex viscosity of from about 140 Pa·s to about    200 Pa·s, wherein the complex viscosity is determined at a constant    strain of 0.5% and a frequency of 1 Hz and a temperature of 25° C.-   368. The composition of any one of 323 to 367, wherein the ratio of    the HVLCM to the solvent in the composition is about 0.6:1 to 1.6:1.-   369. The composition of 368, wherein the ratio of the HVLCM to the    solvent in the composition is about 0.8:1 to 1.5:1.-   370. The composition of 369, wherein the ratio of the HVLCM to the    solvent in the composition is about 0.9:1 to 1.5:1.-   371. The composition of any one of 323 to 370, wherein the    composition comprises:    -   about 35% by weight to about 45% by weight of the HVLCM relative        to the total weight of the composition,    -   about 31% by weight to about 45% by weight of the solvent        relative to the total weight of the composition, and    -   about 2% by weight to about 10% by weight of the network former        relative to the total weight of the composition.-   372. The composition of 371, comprising about 0.1% by weight to    about 8% by weight of a rheology modifier relative to the total    weight of the composition.-   373. The composition of 371 or 372, comprising about 2% by weight to    about 10% by weight of a hydrophilic agent.-   374. The composition of any one of 323 to 373, wherein the    composition comprises:    -   about 39% by weight to about 41% by weight of the HVLCM relative        to the total weight of the composition,    -   about 38% by weight to about 40% by weight of the solvent        relative to the total weight of the composition, and    -   about 4% by weight to about 6% by weight of the network former        relative to the total weight of the composition.-   375. The composition of any one of 323-374, comprising about 2% by    weight to about 3% by weight of a rheology modifier relative to the    total weight of the composition.-   376. The composition of any one of 323-375, comprising about 5% by    weight to about 6% by weight of a hydrophilic agent relative to the    total weight of the composition.-   377. The composition of any one of 323 to 376, wherein the HVLCM is    SAIB, the solvent is triacetin, and the network former is CAB.-   378. The composition of 377, comprising IPM.-   379. The composition of 377 or 378, comprising HEC.-   380. The composition of any one of 323 to 379, wherein the    pharmacologically active agent is present in the composition at    about 2% by weight to about 50% by weight relative to the total    weight of the composition.-   381. The composition of any one of 323 to 380, wherein the    composition is contained within a capsule.-   382. The composition of any one of 323 to 381, wherein the    composition is contained within a capsule comprising    hydroxypropylmethylcellulose.-   383. The composition of any one of 323 to 382, wherein the    composition is contained within a hard capsule comprising    hydroxypropylmethylcellulose.-   384. The composition of any one of 296-310, wherein the opioid is    present in the composition at about 5% by weight relative to the    total weight of the composition.-   385. The composition of any one of 396-311, wherein the composition    does not comprise more than 5% water by weight, based on total    weight of the composition.-   386. The composition of 312, wherein the composition does not    comprise more than 2.5% water by weight, based on total weight of    the composition.-   387. The composition of 312, wherein the composition does not    comprise more than 2.0% water by weight, based on total weight of    the composition.-   388. The composition of any one of 296-311, wherein the composition    comprises water at from about 1.0 to about 2.5% by weight, based on    total weight of the composition.-   389. The composition of 315, wherein the composition comprises water    at from about 1.0 to about 2.0% by weight, based on total weight of    the composition.-   390. The composition of 316, wherein the composition comprises water    at from about 1.0 to about 1.5% by weight, based on total weight of    the composition.-   391. A composition comprising:    -   a pharmacologically active agent;    -   a high viscosity liquid carrier material (HVLCM) having a        viscosity of at least 5000 cP at 37° C. that does not        crystallize neat at 25° C. and 1 atmosphere;    -   a solvent;    -   a network former; and    -   a mineral particle, wherein the HVLCM, the solvent, the network        former, and the mineral particle are present in a ratio        sufficient to reduce inter-capsule variability in an in vitro        release profile of the composition relative to Reference        Formulation A, when assayed in a USP Apparatus 2 dissolution        tester modified to have a 20-mesh basket for containing the        composition.-   392. The composition of 391, wherein the reduction in inter-capsule    variability is evidenced by a % RSD of less than 10% at t=2 hr.-   393. The composition of 391, wherein the reduction in inter-capsule    variability is evidenced by a % RSD of less than 10% at t=6 hr.-   394. The composition of 391, wherein the mineral particle is    selected from talc, bentonite and kaolin.-   395. The composition of 391, wherein the mineral particle is    selected from silicon dioxide, zinc oxide, magnesium oxide, titanium    oxide, and calcium oxide.-   396. The composition of 391, wherein the mineral particle comprises    silicon dioxide.-   397. The composition of 391, wherein the pharmacologically active    agent is selected from opioid, stimulant, and depressant.-   398. The composition of 391, wherein the pharmacologically active    agent is an opioid.-   399. The composition of 391, wherein the pharmacologically active    agent is selected from oxycodone, oxymorphone, hydrocodone, and    hydromorphone, either in the free base form or a pharmaceutically    acceptable salt form thereof.-   400. The composition of 391, wherein the pharmacologically active    agent is oxycodone.-   401. The composition of any one of 391 to 400, wherein the HVLCM is    sucrose acetate isobutyrate (SAIB).-   402. The composition of any one of 391 to 401, comprising about 35%    by weight to about 45% by weight of the HVLCM relative to the total    weight of the composition.-   403. The composition of any one of 391 to 402, wherein the solvent    is selected from triacetin, N-methyl-2-pyrrolidone, 2-pyrrolidone,    dimethylsulfoxide, ethyl lactate, propylene carbonate and    glycofurol.-   404. The composition of any one of 391 to 403, wherein the solvent    comprises triacetin.-   405. The composition of any one of 391 to 403, wherein the solvent    comprises N-methyl-2-pyrrolidone.-   406. The composition of any one of 391 to 403, wherein the solvent    comprises 2-pyrrolidone.-   407. The composition of any one of 391 to 403, wherein the solvent    comprises dimethylsulfoxide.-   408. The composition of any one of 391 to 403, wherein the solvent    comprises ethyl lactate.-   409. The composition of any one of 391 to 403, wherein the solvent    comprises propylene carbonate.-   410. The composition of any one of 391 to 403, wherein the solvent    comprises glycofurol.-   411. The composition of any one of 391 to 410, comprising about 31%    by weight to about 45% by weight of the solvent relative to the    total weight of the composition.-   412. The composition of 411, comprising about 38% by weight to about    41% by weight of the solvent relative to the total weight of the    composition.-   413. The composition of any one of 391 to 412, further comprising a    rheology modifier.-   414. The composition of 413, wherein the rheology modifier is    selected from isopropyl myristate (IPM), caprylic/capric    triglyceride, ethyl oleate, triethyl citrate, dimethyl phthalate and    benzyl benzoate.-   415. The composition of 413, wherein the rheology modifier is IPM.-   416. The composition of 413, wherein the rheology modifier is    caprylic/capric triglyceride.-   417. The composition of 413, wherein the rheology modifier is ethyl    oleate.-   418. The composition of 413, wherein the rheology modifier is    triethyl citrate.-   419. The composition of 413, wherein the rheology modifier is    dimethyl phthalate.-   420. The composition of 413, wherein the rheology modifier is benzyl    benzoate.-   421. The composition of any one of 413-420, comprising about 2% by    weight to about 10% by weight of the rheology modifier relative to    the total weight of the composition.-   422. The composition of any one of 391 to 420, wherein the network    former is selected from cellulose acetate butyrate (CAB), cellulose    acetate phthalate, ethyl cellulose, hydroxypropylmethyl cellulose    and cellulose triacetate.-   423. The composition of any one of 391 to 422, wherein the network    former comprises cellulose acetate butyrate (CAB).-   424. The composition of any one of 391 to 423, wherein the network    former comprises CAB having a number average molecular weight    ranging from 50,000 Daltons to 100,000 Daltons.-   425. The composition of any one of 391 to 424, wherein the network    former comprises CAB having at least one feature selected from a    butyryl content ranging from about 17% to about 41%, an acetyl    content ranging from about 13% to about 30%, and a hydroxyl content    ranging from about 0.5% to about 1.7%.-   426. The composition of any one of 391 to 425, further comprising a    hydrophilic agent.-   427. The composition of 426, wherein the hydrophilic agent is    selected from hydroxyethyl cellulose (HEC), hydroxypropyl cellulose,    caboxymethyl cellulose, polyethylene glycol and    polyvinylpyrrolidone.-   428. The composition of 426, wherein the hydrophilic agent comprises    HEC.-   429. The composition of any one of 391 to 428, wherein the mineral    particle is present in the composition in an amount from about 2.5%    by weight to about 4.0% by weight relative to the total weight of    the composition.-   430. The composition of any one of 391 to 429, wherein the mineral    particle is present in the composition in an amount from about 2.5%    by weight to about 3.5% by weight relative to the total weight of    the composition.-   431. The composition of any one of 391 to 430, wherein the mineral    particle is present in the composition in an amount from about 2.5%    by weight to about 3.2% by weight relative to the total weight of    the composition.-   432. The composition of any one of 391 to 431, wherein the mineral    particle is present in the composition in an amount from about 2.5%    by weight to about 3.0% by weight relative to the total weight of    the composition.-   433. The composition of any one of 391 to 432, wherein the mineral    particle is present in the composition at from about 2.5% by weight    to about 2.9% by weight relative to the total weight of the    composition.-   434. The composition of any one of 391 to 433, wherein the    composition has a complex viscosity of from about 100 Pa·s to about    300 Pa·s, wherein the complex viscosity is determined at a constant    strain of 0.5% and a frequency of 1 Hz and a temperature of 25° C.-   435. The composition of any one of 391 to 434, wherein the    composition has a complex viscosity of from about 120 Pa·s to about    250 Pa·s, wherein the complex viscosity is determined at a constant    strain of 0.5% and a frequency of 1 Hz and a temperature of 25° C.-   436. The composition of any one of 391 to 435, wherein the    composition has a complex viscosity of from about 140 Pa·s to about    200 Pa·s, wherein the complex viscosity is determined at a constant    strain of 0.5% and a frequency of 1 Hz and a temperature of 25° C.-   437. The composition of any one of 391 to 436, wherein the ratio of    the HVLCM to the solvent in the composition is about 0.6:1 to 1.6:1.-   438. The composition of 437, wherein the ratio of the HVLCM to the    solvent in the composition is about 0.8:1 to 1.5:1.-   439. The composition of 438, wherein the ratio of the HVLCM to the    solvent in the composition is about 0.9:1 to 1.5:1.-   440. The composition of any one of 391 to 439, wherein the    composition comprises:    -   about 35% by weight to about 45% by weight of the HVLCM relative        to the total weight of the composition,    -   about 31% by weight to about 45% by weight of the solvent        relative to the total weight of the composition, and    -   about 2% by weight to about 10% by weight of the network former        relative to the total weight of the composition.-   441. The composition of 440, comprising about 0.1% by weight to    about 8% by weight of a rheology modifier relative to the total    weight of the composition.-   442. The composition of 440 or 441, comprising about 2% by weight to    about 10% by weight of a hydrophilic agent.-   443. The composition of any one of 391 to 442, wherein the    composition comprises:    -   about 39% by weight to about 41% by weight of the HVLCM relative        to the total weight of the composition,    -   about 38% by weight to about 40% by weight of the solvent        relative to the total weight of the composition, and    -   about 4% by weight to about 6% by weight of the network former        relative to the total weight of the composition.-   444. The composition of any one of 391-443, comprising about 2% by    weight to about 3% by weight of a rheology modifier relative to the    total weight of the composition.-   445. The composition of any one of 391-444, comprising about 5% by    weight to about 6% by weight of a hydrophilic agent relative to the    total weight of the composition.-   446. The composition of any one of 391 to 445, wherein the HVLCM is    SAIB, the solvent is triacetin, and the network former is CAB.-   447. The composition of 446, comprising IPM.-   448. The composition of 446 or 447, comprising HEC.-   449. The composition of any one of 391 to 448, wherein the    pharmacologically active agent is present in the composition at    about 2% by weight to about 50% by weight relative to the total    weight of the composition.-   450. The composition of any one of 391 to 449, wherein the    composition is contained within a capsule.-   451. The composition of any one of 391 to 450, wherein the    composition is contained within a capsule comprising hydroxypropyl    methylcellulose.-   452. The composition of any one of 391 to 451, wherein the    composition is contained within a hard capsule comprising    hydroxypropyl methylcellulose.-   453. The composition of any one of 391-452, wherein the composition    does not comprise more than 5% water by weight, based on total    weight of the composition.-   454. The composition of 453, wherein the composition does not    comprise more than 2.5% water by weight, based on total weight of    the composition.-   455. The composition of 453, wherein the composition does not    comprise more than 2.0% water by weight, based on total weight of    the composition.-   456. The composition of any one of 391-452, wherein the composition    comprises water at from about 1.0 to about 2.5% by weight, based on    total weight of the composition.-   457. The composition of 456, wherein the composition comprises water    at from about 1.0 to about 2.0% by weight, based on total weight of    the composition.-   458. The composition of 457, wherein the composition comprises water    at from about 1.0 to about 1.5% by weight, based on total weight of    the composition.-   459. A composition comprising:    -   a pharmacologically active agent;    -   a high viscosity liquid carrier material (HVLCM) having a        viscosity of at least 5000 cP at 37° C. that does not        crystallize neat at 25° C. and 1 atmosphere;    -   a solvent;    -   a network former; and    -   a mineral particle, wherein the HVLCM, the solvent, the network        former, and the mineral particle are present in a ratio        sufficient to provide an in vitro release profile characterized        by an inter-capsule variability having a % RSD of less than 10%        at t=2 hr as determined by an in vitro dissolution assay using a        USP Apparatus 2 dissolution tester modified to have a 20-mesh        basket for containing the composition.-   460. A composition comprising:    -   oxycodone at about 5% by weight to about 10% by weight relative        to the total weight of the composition;    -   sucrose acetate isobutyrate (SAIB);    -   triacetin;    -   isopropyl myristate (IPM);    -   cellulose acetate butyrate (CAB);    -   hydroxyethyl cellulose (HEC); and    -   silicon dioxide, wherein the sucrose acetate isobutyrate (SAIB),        triacetin, isopropyl myristate (IPM), cellulose acetate butyrate        (CAB), hydroxyethyl cellulose (HEC), and silicon dioxide, are        present in a ratio sufficient to reduce a storage time-dependent        change in an in vitro release profile of the composition        relative to Reference Formulation A.-   461. The composition of 460, wherein Reference Formulation A    exhibits more than 10% mean drug release decline, a similarity    factor (f₂) of less than 50, when stored at 40° C./75% RH for a one    month period of time relative to its initial release profile.-   462. A composition comprising:    -   oxycodone at about 5% by weight to about 10% by weight relative        to the total weight of the composition;    -   sucrose acetate isobutyrate (SAIB);    -   triacetin;    -   isopropyl myristate (IPM);    -   cellulose acetate butyrate (CAB);    -   hydroxyethyl cellulose (HEC); and    -   silicon dioxide, wherein the sucrose acetate isobutyrate (SAIB),        triacetin, isopropyl myristate (IPM), cellulose acetate butyrate        (CAB), hydroxyethyl cellulose (HEC), and silicon dioxide, are        present in a ratio sufficient to reduce inter-capsule        variability relative to Formulation A when assayed in a USP        Apparatus 2 dissolution tester modified to have a 20-mesh basket        for containing the composition.-   463. The composition of 462, wherein the reduction in inter-capsule    variability is evidenced by a % RSD of less than 10% at t=2 hr.-   464. The composition of 462, wherein the reduction in inter-capsule    variability is evidenced by a % RSD of less than 10% at t=6 hr.-   465. A composition comprising:    -   oxycodone at about 5% by weight to about 10% by weight relative        to the total weight of the composition;    -   sucrose acetate isobutyrate (SAIB);    -   triacetin;    -   isopropyl myristate (IPM);    -   cellulose acetate butyrate (CAB);    -   hydroxyethyl cellulose (HEC); and    -   silicon dioxide, wherein the sucrose acetate isobutyrate (SAIB),        triacetin, isopropyl myristate (IPM), cellulose acetate butyrate        (CAB), hydroxyethyl cellulose (HEC), and silicon dioxide, are        present in a ratio sufficient to provide an in vitro release        profile characterized by an inter-capsule variability having a %        RSD of less than 10% at t=2 hr as determined by an in vitro        dissolution assay using a USP Apparatus 2 dissolution tester        modified to have a 20-mesh basket for containing the        composition.-   466. A composition comprising:    -   a pharmacologically active agent; and    -   combined amounts of a high viscosity liquid carrier material        (HVLCM) having a viscosity of at least 5000 cP at 37° C. that        does not crystallize neat at 25° C. and 1 atmosphere, a solvent,        a rheology modifier, silicon dioxide, and a cellulose acetate        butyrate, wherein the combined amounts are sufficient to        increase reproducibility of release with respect to        inter-capsule variability relative to Reference Formulation A        when assayed in a USP Apparatus 2 dissolution tester modified to        have a 20-mesh basket for containing the composition.-   467. The composition of 466, wherein the increase in reproducibility    of release is evidenced by a % RSD of less than 10% at t=2 hr.-   468. The composition of 466, wherein the increase in reproducibility    of release is evidenced by a % RSD of less than 10% at t=6 hr.-   469. A composition comprising:    -   a pharmacologically active agent; and    -   combined amounts of a high viscosity liquid carrier material        (HVLCM) having a viscosity of at least 5000 cP at 37° C. that        does not crystallize neat at 25° C. and 1 atmosphere, a solvent,        a rheology modifier, silicon dioxide, and a cellulose acetate        butyrate, wherein the combined amounts are sufficient to provide        an in vitro release profile characterized by an inter-capsule        variability having a % RSD of less than 10% at t=2 hr as        determined by an in vitro dissolution assay using a USP        Apparatus 2 dissolution tester modified to have a 20-mesh basket        for containing the composition.-   470. A composition comprising:    -   a pharmacologically active agent; and    -   combined amounts of a high viscosity liquid carrier material        (HVLCM) having a viscosity of at least 5000 cP at 37° C. that        does not crystallize neat at 25° C. and 1 atmosphere, a solvent,        a rheology modifier, silicon dioxide, and a cellulose acetate        butyrate, wherein the combined amounts are sufficient to        increase reproducibility of release with respect to storage time        relative to Reference Formulation A when assayed in a USP        Apparatus 2 dissolution tester modified to have a 20-mesh basket        for containing the composition.-   471. The composition of 470, wherein Reference Formulation A    exhibits more than 10% mean drug release decline, a similarity    factor (f₂) of less than 50, when stored at 40° C./75% RH for a one    month period of time relative to its initial release profile.-   472. A method for treating pain in a subject, the method comprising:    -   orally administering to the subject a composition comprising        -   an opioid;        -   a high viscosity liquid carrier material (HVLCM) having a            viscosity of at least 5000 cP at 37° C. that does not            crystallize neat at 25° C. and 1 atmosphere;        -   a solvent;        -   a network former; and        -   silicon dioxide, wherein the silicon dioxide is present in            the composition in an amount from about 2.4% by weight to            about 5.4% by weight relative to the total weight of the            composition, wherein the composition is formulated for oral            administration, and one or more symptoms or signs associated            with the subject's pain is alleviated.-   473. The method of 472, wherein the opioid is selected from    oxycodone, oxymorphone, hydrocodone, and hydromorphone, either in    the free base form or a pharmaceutically acceptable salt form    thereof-   474. The method of 472 or 473, wherein the opioid is oxycodone.-   475. The method of any one of 472-474, wherein the HVLCM is sucrose    acetate isobutyrate (SAIB).-   476. The method of any one of 472 to 475, wherein the composition    comprises about 35% by weight to about 45% by weight of the HVLCM    relative to the total weight of the composition.-   477. The method of any one of 472-475, wherein the solvent is    selected from triacetin, N-methyl-2-pyrrolidone, 2-pyrrolidone,    dimethylsulfoxide, ethyl lactate, propylene carbonate and    glycofurol.-   478. The method of any one of 472-477, wherein the solvent comprises    triacetin.-   479. The method of any one of 472 to 478, wherein the composition    comprises about 31% by weight to about 45% by weight of the solvent    relative to the total weight of the composition.-   480. The method of 479, wherein the composition comprises about 38%    by weight to about 41% by weight of the solvent relative to the    total weight of the composition.-   481. The method of any one of 472 to 480, wherein the composition    further comprises a rheology modifier.-   482. The method of 481, wherein the rheology modifier is selected    from isopropyl myristate (IPM), caprylic/capric triglyceride, ethyl    oleate, triethyl citrate, dimethyl phthalate and benzyl benzoate.-   483. The method of any one of 472-480, wherein the composition    further comprises IPM.-   484. The method of 483, wherein the composition comprises about 2%    by weight to about 10% by weight of the IPM relative to the total    weight of the composition.-   485. The method of any one of 472-482, wherein the network former is    selected from cellulose acetate butyrate (CAB), cellulose acetate    phthalate, ethyl cellulose, hydroxypropylmethyl cellulose and    cellulose triacetate.-   486. The method of any one of 472 to 485, wherein the network former    comprises CAB.-   487. The method of any one of 472 to 486, wherein the network former    comprises CAB having a number average molecular weight ranging from    66,000 Daltons to 83,000 Daltons.-   488. The method of any one of 472 to 487, wherein the network former    comprises CAB having at least one feature selected from a butyryl    content ranging from about 17% to about 38%, an acetyl content    ranging from about 13% to about 30%, and a hydroxyl content ranging    from about 0.8% to about 1.7%.-   489. The method of any one of 472-488, wherein the composition    comprises a hydrophilic agent.-   490. The method of 489, wherein the hydrophilic agent is selected    from hydroxyethyl cellulose (HEC), hydroxypropyl cellulose,    caboxymethyl cellulose, polyethylene glycol and    polyvinylpyrrolidone.-   491. The method of any one of 472-490, wherein the silicon dioxide    is present in the composition in an amount from about 2.5% by weight    to about 3.5% by weight relative to the total weight of the    composition.-   492. The method of any one of 472-491, wherein the silicon dioxide    is present in the composition in an amount from about 2.5% by weight    to about 3.2% by weight relative to the total weight of the    composition.-   493. The method of any one of 472-492, wherein the silicon dioxide    is present in the composition in an amount from about 2.5% by weight    to about 3.0% by weight relative to the total weight of the    composition.-   494. The method of any one of 472-493, wherein the silicon dioxide    is present in the composition at about 2.5% by weight to about 2.9%    by weight relative to the total weight of the composition.-   495. The method of any one of 472 to 494, wherein the composition    has a complex viscosity of from about 100 Pa·s to about 300 Pa·s,    wherein the complex viscosity is determined at a constant strain of    0.5% and a frequency of 1 Hz and a temperature of 25° C.-   496. The method of any one of 472 to 495, wherein the composition    has a complex viscosity of from about 120 Pa·s to about 250 Pa·s,    wherein the complex viscosity is determined at a constant strain of    0.5% and a frequency of 1 Hz and a temperature of 25° C.-   497. The method of any one of 472 to 496, wherein the composition    has a complex viscosity of from about 140 Pa·s to about 200 Pa·s,    wherein the complex viscosity is determined at a constant strain of    0.5% and a frequency of 1 Hz and a temperature of 25° C.-   498. The method of any one of 472 to 497, wherein the ratio of the    HVLCM to the solvent in the composition is about 0.6:1 to 1.6:1.-   499. The method of 498, wherein the ratio of the HVLCM to the    solvent in the composition is about 0.8:1 to 1.5:1.-   500. The method of 499, wherein the ratio of the HVLCM to the    solvent in the composition is about 0.9:1 to 1.5:1.-   501. The method of any one of 472-500, wherein the composition    comprises:    -   about 35% by weight to about 45% by weight of the HVLCM relative        to the total weight of the composition,    -   about 31% by weight to about 45% by weight of the solvent        relative to the total weight of the composition, and    -   about 2% by weight to about 10% by weight of the network former        relative to the total weight of the composition.-   502. The method of 501, comprising about 0.1% by weight to about 8%    by weight of a rheology modifier relative to the total weight of the    composition.-   503. The method of 501 or 502, comprising about 2% by weight to    about 10% by weight of a hydrophilic agent.-   504. The method of any one of 472 to 503, wherein the composition    comprises:    -   about 39% by weight to about 41% by weight of the HVLCM relative        to the total weight of the composition,    -   about 38% by weight to about 40% by weight of the solvent        relative to the total weight of the composition, and    -   about 4% by weight to about 6% by weight of the network former        relative to the total weight of the composition.-   505. The method of any one of 472-504, comprising about 2% by weight    to about 3% by weight of a rheology modifier relative to the total    weight of the composition.-   506. The method of any one of 472-505, wherein the composition    comprises about 5% by weight to about 6% by weight of a hydrophilic    agent relative to the total weight of the composition.-   507. The method of any one of 472-506, wherein the HVLCM is SAIB,    the solvent is triacetin, and the network former is CAB.-   508. The method of 507, wherein the composition comprises IPM.-   509. The method of 507 or 508, wherein the composition comprises    HEC.-   510. The method of any one of 472 to 509, wherein the    pharmacologically active agent is present in the composition at    about 2% by weight to about 50% by weight relative to the total    weight of the composition.-   511. The method of any one of 472 to 510, wherein the composition is    contained within a capsule.-   512. The method of any one of 472 to 511, wherein the composition is    contained within a capsule comprising hydroxypropyl methylcellulose.-   513. The method of any one of 472 to 512, wherein the composition is    contained within a hard capsule comprising hydroxypropyl    methylcellulose.-   514. The method of any one of 472-513, wherein the composition is    administered no more than twice in a 24-hour period.-   515. The method of any one of 472-514, wherein the composition does    not comprise more than 5% water by weight, based on total weight of    the composition.-   516. The method of 515, wherein the composition does not comprise    more than 2.5% water by weight, based on total weight of the    composition.-   517. The method of 515, wherein the composition does not comprise    more than 2.0% water by weight, based on total weight of the    composition.-   518. The method of any one of 472-514, wherein the composition    comprises water at from about 1.0 to about 2.5% by weight, based on    total weight of the composition.-   519. The method of 518, wherein the composition comprises water at    from about 1.0 to about 2.0% by weight, based on total weight of the    composition.-   520. The method of 519, wherein the composition comprises water at    from about 1.0 to about 1.5% by weight, based on total weight of the    composition.-   521. A method for treating pain in a subject, the method comprising:    -   orally administering to the subject a composition comprising        -   an opioid;        -   sucrose acetate isobutyrate (SAIB);        -   triacetin;        -   isopropyl myristate (IPM);        -   cellulose acetate butyrate (CAB);        -   hydroxyethyl cellulose (HEC); and        -   silicon dioxide, wherein the silicon dioxide is present in            the composition in an amount from about 2.4% by weight to            about 5.4% by weight relative to the total weight of the            composition, wherein the composition is formulated for oral            administration, and one or more symptoms or signs associated            with the subject's pain is alleviated.-   522. The method of 521, wherein the SAIB is present in the    composition in an amount from about 35% by weight to about 45% by    weight relative to the total weight of the composition, the    triacetin is present in the composition in an amount from about 31%    by weight to about 45% by weight relative to the total weight of the    composition, the IPM is present in the composition in an amount from    about 2% by weight to about 10% by weight relative to the total    weight of the composition, the CAB is present in the composition at    about 4% by weight to about 6% by weight relative to the total    weight of the composition, and the HEC is present in the composition    in an amount from about 5% by weight to about 6% by weight relative    to the total weight of the composition.-   523. The method of 521 or 522, wherein the composition comprises    about 38% by weight to about 41% by weight of the triacetin relative    to the total weight of the composition.-   524. The method of any one of 521 to 523, wherein the composition    comprises about 2% by weight to about 3% by weight of the IPM    relative to the total weight of the composition.-   525. The method of any one of 521 to 524, wherein the CAB has a    number average molecular weight ranging from 66,000 Daltons to    83,000 Daltons.-   526. The method of any one of 521 to 525, wherein the network former    comprises CAB having at least one feature selected from a butyryl    content ranging from about 17% to about 38%, an acetyl content    ranging from about 13% to about 30%, and a hydroxyl content ranging    from about 0.8% to about 1.7%.-   527. The method of any one of 521-526, wherein the silicon dioxide    is present in the composition in an amount from about 2.5% by weight    to about 3.2% by weight relative to the total weight of the    composition.-   528. The method of any one of 521-527, wherein the silicon dioxide    is present in the composition in an amount from about 2.5% by weight    to about 3.0% by weight relative to the total weight of the    composition.-   529. The method of any one of 521-528, wherein the silicon dioxide    is present in the composition in an amount from about 2.5% by weight    to about 3.0% by weight relative to the total weight of the    composition.-   530. The method of any one of 521-529, wherein the silicon dioxide    is present in the composition in an amount from about 2.5% by weight    to about 2.9% by weight relative to the total weight of the    composition.-   531. The method of any one of 105 to 530, wherein the composition    has a complex viscosity of from about 100 Pa·s to about 300 Pa·s,    wherein the complex viscosity is determined at a constant strain of    0.5% and a frequency of 1 Hz and a temperature of 25° C.-   532. The method of any one of 105 to 531, wherein the composition    has a complex viscosity of from about 120 Pa·s to about 250 Pa·s,    wherein the complex viscosity is determined at a constant strain of    0.5% and a frequency of 1 Hz and a temperature of 25° C.-   533. The method of any one of 105 to 532, wherein the composition    has a complex viscosity of from about 140 Pa·s to about 200 Pa·s,    wherein the complex viscosity is determined at a constant strain of    0.5% and a frequency of 1 Hz and a temperature of 25° C.-   534. The method of any one of 521-533, wherein the opioid is    selected from oxycodone, oxymorphone, hydrocodone, and    hydromorphone, either in the free base form or a pharmaceutically    acceptable salt form thereof.-   535. The method of any one of 521-534, wherein the opioid is    oxycodone.-   536. The method of any one of 521-535, wherein the opioid is present    in the composition at about 5% by weight relative to the total    weight of the composition.-   537. The method of any one of 521-536, wherein the composition is    encapsulated for oral administration.-   538. The method of any one of 521 to 537, wherein the composition is    contained within a capsule.-   539. The method of any one of 521 to 538, wherein the composition is    contained within a capsule comprising hydroxypropyl methylcellulose.-   540. The method of any one of 521 to 539, wherein the composition is    contained within a hard capsule comprising hydroxypropyl    methylcellulose.-   541. The method of any one of 521-537, wherein the composition is    administered no more than twice in a 24-hour period.-   542. The method of any one of 521-541, wherein the composition does    not comprise more than 5% water by weight, based on total weight of    the composition.-   543. The method of 542, wherein the composition does not comprise    more than 2.5% water by weight, based on total weight of the    composition.-   544. The method of 542, wherein the composition does not comprise    more than 2.0% water by weight, based on total weight of the    composition.-   545. The method of any one of 521-541, wherein the composition    comprises water at from about 1.0 to about 2.5% by weight, based on    total weight of the composition.-   546. The method of 545, wherein the composition comprises water at    from about 1.0 to about 2.0% by weight, based on total weight of the    composition.-   547. The method of 546, wherein the composition comprises water at    from about 1.0 to about 1.5% by weight, based on total weight of the    composition.-   548. A method for treating pain in a subject, the method comprising:    -   orally administering to the subject a composition comprising        -   oxycodone;        -   about 35% by weight to about 45% sucrose acetate isobutyrate            (SAIB) relative to the total weight of the composition;        -   about 31% by weight to about 45% of triacetin relative to            the total weight of the composition;        -   about 2% by weight to about 10% by weight of isopropyl            myristate (IPM) relative to the total weight of the            composition;        -   about 4% to about 6% by weight of cellulose acetate butyrate            (CAB) relative to the total weight of the composition;        -   about 5% by weight to about 6% by weight of hydroxyethyl            cellulose (HEC) relative to the total weight of the            composition; and        -   about 2.4% by weight to about 5.4% by weight of silicon            dioxide relative to the total weight of the composition,            wherein one or more symptoms or signs associated with the            subject's pain is alleviated.-   549. A method for treating pain in a subject, the method comprising:    -   orally administering to the subject a composition comprising        -   oxycodone;        -   about 39% by weight to about 41% sucrose acetate isobutyrate            (SAIB) relative to the total weight of the composition;        -   about 38% by weight to about 41% of triacetin relative to            the total weight of the composition;        -   about 2% by weight to about 3% by weight of isopropyl            myristate (IPM) relative to the total weight of the            composition;        -   about 4% to about 6% by weight of cellulose acetate butyrate            (CAB) relative to the total weight of the composition;        -   about 5% by weight to about 6% by weight of hydroxyethyl            cellulose (HEC) relative to the total weight of the            composition; and        -   about 2.5% by weight to about 3.2% by weight of silicon            dioxide relative to the total weight of the composition,            wherein one or more symptoms or signs associated with the            subject's pain is alleviated.-   550. A method for treating pain in a subject, the method comprising:    -   orally administering to the subject a composition comprising        -   about 5% by weight of oxycodone relative to the total weight            of the composition;        -   about 39% by weight to about 41% sucrose acetate isobutyrate            (SAIB) relative to the total weight of the composition;        -   about 38% by weight to about 41% of triacetin relative to            the total weight of the composition;        -   about 2% by weight to about 3% by weight of isopropyl            myristate (IPM) relative to the total weight of the            composition;        -   about 4% to about 6% by weight of cellulose acetate butyrate            (CAB) relative to the total weight of the composition;        -   about 5% by weight to about 6% by weight of hydroxyethyl            cellulose (HEC) relative to the total weight of the            composition; and        -   about 2.5% by weight to about 3.2% by weight of silicon            dioxide relative to the total weight of the composition,            wherein one or more symptoms or signs associated with the            subject's pain is alleviated.-   551. A method for treating pain in a subject, the method comprising:    -   orally administering to the subject a composition comprising        -   oxycodone at about 5% by weight relative to the total weight            of the composition;        -   sucrose acetate isobutyrate (SAIB) at about 40% by weight            relative to the total weight of the composition;        -   triacetin at about 39% by weight relative to the total            weight of the composition;        -   isopropyl myristate (IPM) at about 2.5% by weight relative            to the total weight of the composition;        -   cellulose acetate butyrate (CAB) at about 4.5% by weight or            4.7% by weight relative to the total weight of the            composition;        -   hydroxyethyl cellulose (HEC) at about 5.5% by weight            relative to the total weight of the composition; and        -   silicon dioxide, wherein the silicon dioxide is present in            the composition at about 2.9% by weight relative to the            total weight of the composition, wherein the composition is            formulated for oral administration, wherein one or more            symptoms or signs associated with the subject's pain is            alleviated.-   552. The method of 550, wherein the composition is contained within    a capsule.-   553. The method of 550 or 552, wherein the composition is contained    within a capsule comprising hydroxypropyl methylcellulose.-   554. The method of any one of 550 to 553, wherein the composition is    contained within a hard capsule comprising hydroxypropyl    methylcellulose.-   555. The method any one of 550-554, wherein the composition is    administered no more than twice in a 24-hour period.-   556. A method of orally administering a composition, comprising:    -   improving reproducibility of an in vitro release profile of a        composition by including about 2.4% by weight to about 5.4% by        weight, relative to the total weight of the composition, of        mineral particle in the composition, wherein the composition        also includes a pharmacologically active agent, a high viscosity        liquid carrier material (HVLCM) having a viscosity of at least        5000 cP at 37° C. that does not crystallize neat at 25° C. and 1        atmosphere, a solvent, and a network former; and    -   orally administering the composition.-   557. A method of orally administering a composition, comprising:    -   decreasing the variability of an in vitro release profile of a        composition by including about 2.4% by weight to about 5.4% by        weight, relative to the total weight of the composition, of        mineral particle in the composition, wherein the composition        also includes a pharmacologically active agent, a high viscosity        liquid carrier material (HVLCM) having a viscosity of at least        5000 cP at 37° C. that does not crystallize neat at 25° C. and 1        atmosphere, a solvent, and a network former; and    -   orally administering the composition.-   558. A method of orally administering an encapsulated composition,    comprising:    -   forming a composition comprising:        -   a pharmacologically active agent,        -   a high viscosity liquid carrier material (HVLCM) having a            viscosity of at least 5000 cP at 37° C. that does not            crystallize neat at 25° C. and 1 atmosphere,        -   a solvent,        -   a network former, and        -   a mineral particle, wherein the mineral particle is present            in the composition in an amount from about 2.4% by weight to            about 5.4% by weight relative to the total weight of the            composition;    -   improving an in vitro release profile of the composition by        encapsulating the composition in a capsule comprising        hydroxypropyl methylcellulose to form an encapsulated        composition; and    -   orally administering the encapsulated composition.-   559. A method of orally administering an encapsulated composition,    comprising:    -   forming a composition comprising:        -   a pharmacologically active agent,        -   a high viscosity liquid carrier material (HVLCM) having a            viscosity of at least 5000 cP at 37° C. that does not            crystallize neat at 25° C. and 1 atmosphere,        -   a solvent,        -   a network former, and        -   a mineral particle, wherein the mineral particle is present            in the composition in an amount from about 2.4% by weight to            about 5.4% by weight relative to the total weight of the            composition;    -   reducing exposure of the composition to water by encapsulating        the composition in a capsule comprising hydroxypropyl        methylcellulose to form an encapsulated composition; and    -   orally administering the encapsulated composition.-   560. The composition of any one of 1-112 and 228-471, wherein the    solvent is selected from triacetin, N-methyl-2-pyrrolidone,    2-pyrrolidone, dimethylsulfoxide, ethyl lactate, propylene carbonate    and glycofurol and mixtures thereof-   561. The composition of 560, wherein the solvent comprises    triacetin.-   562. The composition of 561, wherein the solvent is triacetin.-   563. The composition of any one of 1-112, 228-471 and 560-562,    wherein the rheology modifier is selected from isopropyl myristate    (IPM), caprylic/capric triglyceride, ethyl oleate, triethyl citrate,    dimethyl phthalate and benzyl benzoate.-   564. The composition of 563, wherein the rheology modifier is    isopropyl myristate (IPM).-   565. The composition of any one of 1-112, 228-471 and 560-564,    wherein the cellulose acetate butyrate is a CAB having a number    average molecular weight ranging from 50,000 Daltons to 100,000    Daltons.-   566. The composition of any one of 1-112, 228-471 and 560-565,    wherein the cellulose acetate butyrate is a CAB having at least one    feature selected from a butyryl content ranging from about 17% to    about 41%, an acetyl content ranging from about 13% to about 30%,    and a hydroxyl content ranging from about 0.5% to about 1.7%.-   567. The composition of any one of 1-112, 228-471 and 560-566,    comprising a surfactant.-   568. The composition of 567, wherein the surfactant is saturated    polyglycolized glyceride.-   569. The composition of any one of 1-112, 228-471 and 560-568,    comprising a hydrophilic agent.-   570. The composition of 569, wherein the hydrophilic agent is    selected from hydroxyethyl cellulose (HEC), hydroxypropyl cellulose,    caboxymethyl cellulose, polyethylene glycol and    polyvinylpyrrolidone.-   571. The composition of any one of 569-570, wherein the hydrophilic    agent comprises HEC.-   572. The composition of any one of 1-112, 228-471 and 560-571,    wherein the composition has a complex viscosity of from about 100    Pa·s to about 300 Pa·s, wherein the complex viscosity is determined    at a constant strain of 0.5% and a frequency of 1 Hz and a    temperature of 25° C.-   573. The composition of any one of 1-112, 228-471 and 560-572,    wherein the composition has a complex viscosity of from about 120    Pa·s to about 250 Pa·s, wherein the complex viscosity is determined    at a constant strain of 0.5% and a frequency of 1 Hz and a    temperature of 25° C.-   574. The composition of any one of 1-112, 228-471 and 560-573,    wherein the composition has a complex viscosity of from about 140    Pa·s to about 200 Pa·s, wherein the complex viscosity is determined    at a constant strain of 0.5% and a frequency of 1 Hz and a    temperature of 25° C.-   575. The composition of any one of 1-112, 228-471 and 560-574,    wherein the pharmacologically active agent is present in the    composition in an amount from about 0.1% by weight to about 30% by    weight relative to the total weight of the composition.-   576. The composition of 575, wherein the pharmacologically active    agent is present in the composition in an amount from about 1% by    weight to about 10% by weight relative to the total weight of the    composition.-   577. The composition of any one of 1-112, 228-471 and 560-576,    wherein the mineral particle is present in the composition in an    amount from about 2.4% by weight to about 5.4% by weight relative to    the total weight of the composition.-   578. The composition of 577, wherein the mineral particle is present    in the composition in an amount from about 2.5% by weight to about    4.0% by weight relative to the total weight of the composition.-   579. The composition of 577, wherein the mineral particle is present    in the composition in an amount from about 2.5% by weight to about    3.5% by weight relative to the total weight of the composition.-   580. The composition of 577, wherein the mineral particle is present    in the composition in an amount from about 2.5% by weight to about    3.2% by weight relative to the total weight of the composition.-   581. The composition of 577, wherein the mineral particle is present    in the composition in an amount from about 2.5% by weight to about    3.0% by weight relative to the total weight of the composition.-   582. The composition of 577, wherein the mineral particle is present    in the composition at from about 2.5% by weight to about 2.9% by    weight relative to the total weight of the composition.-   583. A composition as defined in any one of 1-112, 228-471 and    560-582, for use as a medicament.-   584. A composition as defined in any one of 1-112, 228-471 and    560-582, for use in a method of treating pain, wherein the    composition comprises an opioid.-   585. Use of a composition as defined in any one of 1-112, 228-471    and 560-582 for the manufacture of a medicament for treating pain,    wherein the composition comprises an opioid.-   586. A method for treating pain in a subject, the method comprising    administering to the subject a composition as defined in any one of    1-112, 228-471 and 560-582, wherein the composition comprises an    opioid and wherein one or more symptoms or signs associated with the    subject's pain is alleviated.-   587. A composition comprising:    -   a pharmacologically active agent;    -   a high viscosity liquid carrier material (HVLCM) having a        viscosity of at least 5000 cP at 37° C. that does not        crystallize neat at 25° C. and 1 atmosphere; and    -   a cellulose acetate butyrate,    -   wherein the composition is encapsulated within a        hydroxypropylmethylcellulose capsule, and    -   wherein the composition within the capsule comprises less than        5% water by weight, based on total weight of the composition        within the capsule.-   588. A composition comprising:    -   a pharmacologically active agent;    -   a high viscosity liquid carrier material (HVLCM) having a        viscosity of at least 5000 cP at 37° C. that does not        crystallize neat at 25° C. and 1 atmosphere;    -   a network former; and    -   a mineral particle, wherein the mineral particle is present in        the composition in an amount from about 2.5% by weight to about        3.0% by weight relative to the total weight of the composition.-   589. A composition comprising:    -   an opioid;    -   sucrose acetate isobutyrate (SAIB);    -   triacetin;    -   isopropyl myristate (IPM);    -   cellulose acetate butyrate (CAB), wherein the CAB has a number        average molecular weight ranging from 66,000 Daltons to 83,000        Daltons, and wherein the CAB has at least one feature selected        from a butyryl content ranging from about 17% to about 38%, an        acetyl content ranging from about 13% to about 30%, and a        hydroxyl content ranging from about 0.8% to about 1.7%;    -   hydroxyethyl cellulose (HEC); and    -   silicon dioxide, wherein the silicon dioxide is present in the        composition in an amount from about 2.5% by weight to about 3.0%        by weight relative to the total weight of the composition.-   590. The composition of 589, wherein the SAIB is present in the    composition in an amount from about 35% by weight to about 45% by    weight relative to the total weight of the composition, the    triacetin is present in the composition in an amount from about 31%    by weight to about 45% by weight relative to the total weight of the    composition, the IPM is present in the composition in an amount from    about 2% by weight to about 10% by weight relative to the total    weight of the composition, the CAB is present in the composition at    about 4% to about 6% by weight relative to the total weight of the    composition, and the HEC is present in the composition in an amount    from about 5% by weight to about 6% by weight relative to the total    weight of the composition.-   591. The composition of 589 or 590, comprising about 38% by weight    to about 41% by weight of the triacetin relative to the total weight    of the composition.-   592. The composition of any one of 589 to 591, comprising about 2%    by weight to about 3% by weight of the IPM relative to the total    weight of the composition.-   593. The composition of any one of 589 to 592, wherein the    composition has a complex viscosity of from about 100 Pa·s to about    300 Pa·s, wherein the complex viscosity is determined at a constant    strain of 0.5% and a frequency of 1 Hz and a temperature of 25° C.-   594. The composition of any one of 589 to 593, wherein the    composition has a complex viscosity of from about 120 Pa·s to about    250 Pa·s, wherein the complex viscosity is determined at a constant    strain of 0.5% and a frequency of 1 Hz and a temperature of 25° C.-   595. The composition of any one of 589 to 594, wherein the    composition has a complex viscosity of from about 140 Pa·s to about    200 Pa·s, wherein the complex viscosity is determined at a constant    strain of 0.5% and a frequency of 1 Hz and a temperature of 25° C.-   596. The composition of any one of 589 to 595, wherein the opioid is    selected from oxycodone, oxymorphone, hydrocodone, and    hydromorphone, either in the free base form or a pharmaceutically    acceptable salt form thereof.-   597. The composition of any one of 589 to 596, wherein the opioid is    oxycodone.-   598. The composition of any one of 589 to 597, wherein the opioid is    present in the composition at about 5% by weight relative to the    total weight of the composition.-   599. The composition of any one of 589 to 598, wherein the    composition does not comprise more than 5% water by weight, based on    total weight of the composition.-   600. The composition of 599, wherein the composition does not    comprise more than 2.5% water by weight, based on total weight of    the composition.-   601. The composition of 599, wherein the composition does not    comprise more than 2.0% water by weight, based on total weight of    the composition.-   602. The composition of any one of 589 to 601, wherein the    composition comprises water at from about 1.0 to about 2.5% by    weight, based on total weight of the composition.-   603. The composition of 602, wherein the composition comprises water    at from about 1.0 to about 2.0% by weight, based on total weight of    the composition.-   604. The composition of 603, wherein the composition comprises water    at from about 1.0 to about 1.5% by weight, based on total weight of    the composition.

EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the present invention, and are not intended to limit thescope of what the inventors regard as their invention nor are theyintended to represent that the experiments below are all or the onlyexperiments performed. Efforts have been made to ensure accuracy withrespect to numbers used (e.g. amounts, temperature, etc.) but someexperimental errors and deviations should be accounted for. Unlessindicated otherwise, parts are parts by weight, molecular weight isweight average molecular weight, temperature is in degrees Celsius, andpressure is at or near one atmosphere. Standard abbreviations may beused, e.g., s or sec, second(s); min, minute(s); h or hr, hour(s); andthe like.

Example 1: Time-Dependent Changes in Drug Release Performance ofReference Formulation

Reference Formulation A is a capsule product that provides extendedrelease of oral oxycodone. The product is formulated to resist tamperingand abuse. Although the product is a semi-solid matrix, the compositionis manufactured by a standard liquid-fill manufacturing process. Acommon viscous composition of the active pharmaceutical ingredient(API), colloidal silicon dioxide (CSD) and hydroxyethyl cellulose (HEC)suspended in a cellulose acetate butyrate (CAB)/sucrose acetateisobutyrate (SAIB)/triacetin (TA)/isopropyl myristate (IPM)/Butylatedhydroxytoluene (BHT) solution is filled into a range of capsule sizes toaccommodate various dosage strengths.

The composition of Reference Formulation A is as provided below in Table1A.

TABLE 1A Component Function % w/w Micronized Active Pharmaceutical 5.13oxycodone base Ingredient Sucrose acetate An esterified sucrose 40.98isobutyrate derivative, that is (SAIB) a high viscosity, hydrophobiccarrier molecule, which is the base component in the extended releasematrix Triacetin (TA) Hydrophilic solvent that 27.32 participates in thedissolution or suspension of other components in the extended releasematrix Isopropyl Rheology modifier that 14.23 Myristate participates inthe (IPM) control of drug diffusion from the extended release matrixCellulose acetate Polymer additive for 4.74 butyrate (CAB) abusedeterrence and extended release Hydroxyethyl Non-ionic, water soluble5.69 cellulose polymer that participates (HEC) in the control of drugdiffusion from the extended release matrix Colloidal silicon Suspendingagent, 1.90 dioxide (CSD) viscosity modifier Butylated Antioxidant 0.02hydroxytoluene (BHT) Hard shell capsule Dosage form encapsulationGelatin

In vitro analysis of Reference Formulation A has shown that it mayexhibit time-dependent changes in drug release performance. This isshown, for example, in FIG. 1A, wherein Reference Formulation A (withBHT) stored at 25° C./60% RH for a 22 months period exhibited a decreasein the mean release profile for oxycodone.

Example 2A: Gelatin vs. HPMC Capsules

It was hypothesized that phase immiscibility could be responsible forthe time dependent changes in drug release performance observed forReference Formulation A. It was further hypothesized that reducing theamount of available water by changing the capsule shell from gelatin(˜13-16% w/w water) to HPMC (˜4-6% w/w water) could minimize theseeffects.

Materials and Methods

Dissolution data utilizing the Apparatus 2 method (described below) forReference Formulation A (without BHT) in gelatin or HPMC capsules storedup to 12 months at 25° C./60% RH, 30° C./65% RH and 40° C./75% RH areshown in FIG. 1B, Panels A and B.

Twelve capsules from each formulation were tested with USP Apparatus 2to evaluate the effect on inter-capsule dissolution variability. Therelease rate of oxycodone base was determined using a USP Apparatus 2dissolution tester. Dissolution medium containing 1000 ml 0.1 N HCl with0.5% (w/w) SDS was maintained at 37° C. with 100 rpm paddle speed overthe course of the 24 hour dissolution test. A 20 mesh screen hangingbasket was incorporated to hold the test article and the paddle speedwas set to 100 rpm. The standard sampling time points were 0.5, 2, 3, 6,12 and 24 hours. A 1 mL sample was taken at each time point and assayedusing reverse-phase HPLC at 240 nm wavelength. The mobile phase included0.35% (w/v) SDS/0.7% (v/v) acetic acid/44% (v/v) acetonitrile in water.

Separately, the total water content of a freshly prepared ReferenceFormulation A formulation in gelatin vs. HPMC capsules was determined.Two preparations were tested for each formulation. The % water (ormoisture) was determined by Karl Fischer Coulometric Apparatus and eachpreparation utilized 5 capsules.

Results

The results for the dissolution experiments are provided in FIG. 1B,Panels A and B. As shown in Panel A, Reference Formulation A in gelatincapsules exhibits a decrease in the mean release profile followingstorage for 12 months at 25° C., 6 months at 30° C., 6 months at 40° C.and 3 months at 40° C. relative to the initial release profile. Incontrast, Reference Formulation A in HPMC capsules exhibited a morestable dissolution profile following storage under the above conditions,with the exception of the 40° C. storage conditions. Inter-capsuledissolution variability was not significantly reduced for Formulation Ain HPMC relative to Formulation A in gelatin under the above testingconditions.

The total average water content of Reference Formulation A in gelatinvs. HPMC capsules was found to be 2.2% w/w vs. 1.4% w/w respectively.

Example 2B: Gelatin vs. HPMC Capsules

This study compared two lots of Formulation A (40 mg) prepared withoutBHT and with the same bulk mass filled into size 00 Licaps® (gelatin)(Lot #1) and Vcaps® Plus (HPMC) capsules (Lot #2). The lots were testedfor in vitro dissolution and viscoelastic parameters. In addition, thecapsule shells were evaluated by Karl Fischer titration for itspotential property change.

Materials and Methods

Dissolution Testing

Two separate tests of the two lots were performed after storage of thelots for approximately 12 months at 25° C./60% RH. The release rate ofoxycodone base was determined using a USP Apparatus 3 dissolutiontester. Dissolution medium containing 250 ml 0.1 N HCl with 0.02% (w/w)SDS was maintained at 37° C. with 45 dpm (dips per minute) over thecourse of the 24 hour dissolution test. An glass inner sample tube withtwo ends covered with 20 mesh SS316 was incorporated to hold the testarticle. The standard sampling time points were 0.5, 2, 3, 6, 12 and 24hours. A 1 mL sample was taken at each time point and assayed usingreverse-phase HPLC at 240 nm wavelength. The mobile phase included 0.35%(w/v) SDS/0.7% (v/v) acetic acid/44% (v/v) acetonitrile in water.

The results of the dissolution testing experiment are provided in Tables1B-1D below and FIGS. 1C and 1D.

Rheology Testing

The rheology test was carried out in parallel plates (PP25) at 25° C.using an Anton Paar MCR301 rheometer. The sample was exposed to aconstant angular frequency (10 s⁻¹) of increasing dynamic strain (0.1 to100%).

Water Content by Karl Fischer Titration

Water content of the capsule shell of the two lots was evaluated by KarlFischer titration using an AquaStar C3000 Karl Fischer CoulometricTitrator. In this experiment, the formulation was completely exuded fromthe capsule. The capsule shell was cut into small pieces and placedinside a clear sample vial. The vial was crimped with a metal seal cap.In a second vial, which was used as a blank sample, a sufficient amountof anhydrous methanol was transferred to the vial, and the vial wascrimped with a metal seal cap. Approximately 1.2 mL of anhydrousmethanol from the second vial was added to the sample vial and theweight of methanol introduced was recorded. The sample vial was placedin a mechanical shaker mixing at 300 rpm for about 60 minutes. Thepercentage water content in the sample was determined by weight gainedand calculated against methanol standards.

Results

Dissolution Testing Results

The results of the dissolution testing are provided in Tables 1B-1Dbelow and in FIGS. 1C and 1D.

TABLE 1B Time point (hour) 0.5 2 3 6 12 24 Test 1 Dissolution Results,Lot # 1 (n = 6) in gelatin capsules 1 21 39 46 62 76 85 2 29 52 59 72 8389 3 23 45 53 69 81 86 4 21 40 48 65 83 88 5 19 36 43 57 76 85 6 19 4354 70 81 85 Mean 22 43 51 66 80 86 SD 4 6 6 6 3 2 % RSD 18 14 12 9 4 2Test 2 Dissolution Results, Lot # 1 (n = 12) in gelatin capsules 1 27 4957 72 84 88 2 29 51 60 74 86 91 3 24 45 52 68 78 84 4 22 39 45 60 75 855 24 41 49 63 81 89 6 24 43 50 65 82 90 7 22 46 53 66 78 85 8 21 38 4356 70 83 9 31 54 62 74 85 89 10  30 51 58 72 85 91 11  24 50 58 70 82 8912  22 39 45 58 74 88 Mean 25 45 53 66 80 88 SD 4 6 6 6 5 3 % RSD 16 1313 9 6 3

TABLE 1C Test 1 Dissolution Results, Lot # 2 (n = 6) in HPMC capsulesTime point (hour) 0.5 2 3 6 12 24 1 17 45 55 73 85 88 2 18 53 65 82 9090 3 20 35 41 53 70 83 4 14 34 45 63 78 85 5 18 38 46 63 80 86 6 19 4553 67 81 88 Mean 18 42 51 67 81 87 SD 2 7 9 10 7 3 % RSD 11 17 18 15 9 3

TABLE 1D Test 2, Dissolution Results, Lot # 2 (n = 12) in HPMC capsulesTime point (hour) 0.5 2 3 6 12 24 1 18 48 61 80 88 91 2 18 30 34 43 6078 3 10 29 37 54 73 87 4 18 42 51 69 84 90 5 18 33 43 60 81 88 6 16 3747 68 83 89 7 21 45 55 77 90 94 8 20 42 53 73 86 91 9 19 39 49 71 88 9210  20 50 60 74 84 89 11  22 58 70 85 93 93 12  29 54 65 79 90 93 Mean19 42 52 69 83 90 SD 4 9 11 12 9 4 % RSD 21 21 21 17 11 4

FIG. 1C illustrates the dissolution profiles for the data provided inTables 1B and 1C. The dissolution profiles for both the gelatin and HPMClots were very similar between the two tests. However, the variation washigher in general for the HPMC lot (FIG. 1D). During the first test,visual observations and photographic evidences were taken at 30 minutesand 20 hours. At 30 minutes, the HPMC lot remained in one single piecewhile the gelatin lot broke into fragments. However, at the later time(20 hours) the HPMC lot was seen in more small sized pieces. Withoutintending to be bound by any particular theory, presumably the HPMC lotwas more prone to fragmentation after being exposed to the aqueousmedium and the fragmentation rate might be more variable than thegelatin capsules.

Rheology Testing Results

Table 1E summarizes the viscoelastic outputs of lots 1 and 2 at thelinear viscoelastic (LVE) range. The absolute differences of viscosityη*, storage modulus G′, and loss modulus G″ were 7 Pa·s, 43 Pa, and 56Pa, respectively lower for the HPMC lot than the gelatin lot. Theviscosity differences between the type of capsules are greater than theanalytical method variation, which has an estimated standard deviationof approximately ±2 Pa·s, 8 Pa and 14 Pa for η*, G′ and G″,respectively. Although the Formulation A (without BHT) stored in gelatincapsules had a higher viscosity value than the formulation stored inHPMC capsules, this difference did not appear to influence theirdissolution profiles.

TABLE 1E all values at LVE range Complex viscosity Storage Loss DampingYield η* modulus modulus factor Stress¹ Sample (Pa · s) G′ (Pa) G″ (Pa)tanδ (Pa) Lot #1 (Licaps) 63 308 553 1.80 55.3 Lot #2 (Vcaps 56 265 4971.87 58.7 Plus) Absolute 7 43 56 −0.07 −3.4 difference ¹at 5% toleranceof storage modulus G′

Water Content Results

The results of the Karl Fischer Titration are summarized in Tables 1Fand 1G below. The water content for the intact non-used capsule shellswas found to be as anticipated, i.e. 15% for the gelatin shell and 5.9%for the HPMC shell. The water contents for the Formulation A (withoutBHT) exposed capsule shells were 3.5% lower for the gelatin lot (11.5%)and 1.6% lower for the HPMC lot (4.3%), compared to the respectiveintact capsules. The Formulation A (without BHT) gelatin capsule shellslost more water than the Formulation A (without BHT) HPMC capsuleshells. Without intending to be bound by any particular theory, thegreater water content reduction for the gelatin lot may have occurredbetween the shell and the bulk mass.

TABLE 1F Water Content of Lot #1 (gelatin) by Karl Fischer TitrationWeight of the Water content Sample ID Capsule (g) (%) Change (%) Intactempty Licaps 0.120 15.0 — #1 (Licaps) 0.098 11.2 −3.8 #2 (Licaps) 0.11611.3 −3.7 #3 (Licaps) 0.118 12.0 −3.0 Average 0.111 11.5 −3.5 Standarddeviation 0.011 0.4 0.4 % CV 9.5 3.7 −12.2

TABLE 1G Water Content of Lot #2 (HPMC) by Karl Fischer Titration Weightof the Water content Sample ID Capsule (g) (%) Change (%) Intact emptyVcaps Plus 0.119 5.9 — #1 (Vcaps Plus) 0.115 4.2 −1.7 #2 (Vcaps Plus)0.126 4.4 −1.6 #3 (Vcaps Plus) 0.129 4.3 −1.6 Average 0.123 4.3 −1.6Standard deviation 0.007 0.1  0.1 % CV 6.1  1.8 −4.8

Example 3: Preparation of Extended Release Oxycodone Compositions for PKand BA Analysis

Compositions were prepared, for example, as follows to provide thecompositions indicated in Table 2 (below). Sucrose Acetate Isobutyrate(SAIB) was transferred into a Ross mixer at an elevated temperature (50°C.) and dissolved in triacetin (TA) and isopropyl myristate (IPM) anduniformly mixed. When present in the composition, butylatedhydroxytoluene (BHT) was added prior to uniformly mixing with TA andIPM. Colloidal silicon dioxide (CSD) particles were added into the SAIBsolution in the Ross mixer and were dispersed uniformly. Celluloseacetate butyrate (CAB) particles were sieved and fed into the Ross mixerand dispersed and dissolved in the content of the mixer at the elevatedtemperature. The oxycodone particles were introduced into the Ross mixerand dispersed in the content of the mixer, keeping the same processtemperature. Hydroxyethyl cellulose (HEC) was then added into the Rossmixer and dispersed. In order to assure complete dispersion of allparticles (oxycodone, SiO₂, HEC), high shear mixers (dispenser andemulsifier) may be used for pre-set time periods after the introductionof these solid particles into the Ross mixer.

For the capsule filling operation, the compositions were transferredfrom the Ross mixer via a temperature controlled (or insulated) (at50-60° C.) pump and hoses to the capsule filling equipment. Thetemperature of the compositions was maintained at 50-60° C. during thecapsule filling operations.

Individual compositions were encapsulated within size 4 (5 mg dose) orsize 00 (40 mg dose) gelatin or HPMC capsules. Encapsulation wasachieved using a Capsugel CFS 1000™ apparatus. It was observed thatincreasing the temperature of the composition and the filling pump,e.g., from about 60° C. to about 75° C., reduced the stringiness of thecomposition, thereby facilitating the separation of the composition fromthe nozzle into the capsule shell and allowing clean movement to thenext capsule station. The reduced stringiness of the composition alsoallowed the motor speed setting (fill rate) to be increased, e.g., to amotor speed set point range of about 50% to about 60% (500-600 capsulesper hour). Size 00 capsules were successfully filled using, e.g., a 1.8mm filling nozzle. Size 4 capsules were successfully filled using, e.g.,a 2.0-2.2 mm nozzle. An exemplary composition preparation andencapsulation method is depicted graphically in FIG. 2.

The compositions indicated in Table 2 (below) were prepared for use inExamples 4-6 below. Composition components were blended and individualcompositions were encapsulated within gelatin or HPMC capsules asdescribed above.

TABLE 2 % w/w of component of each formulation FormulationIdentification 1 Reference (Reference Formulation Formulation A inGelatin A in HPMC without without Composition BHT) BHT) 2 3 4 5 6 7 8 9Micronized 5.13 5.13 5.13 5.13 5.13 5.13 5.13 5.13 5.13 5.13 oxycodonebase Sucrose 40.99 40.99 46.69 48.11 40.98 40.98 36.74 38.98 40.38 39.98acetate isobutyrate (SAIB) Triacetin 27.32 27.32 27.32 27.31 32.55 39.0837.56 39.08 39.08 39.08 (TA) Isopropyl 14.23 14.23 14.23 7.12 9.00 2.488.25 2.48 2.48 2.48 Myristate (IPM) Cellulose 4.74 4.74 4.74 4.74 4.744.74 4.74 4.74 4.74 4.74 acetate butyrate (CAB) Hydroxyethyl 5.69 5.690.00 5.69 5.69 5.69 5.69 5.69 5.69 5.69 cellulose (HEC) Colloidal 1.901.90 1.90 1.90 1.90 1.90 1.90 3.90 2.50 2.90 silicon dioxide (CSD)Capsule Shell Gelatin HPMC HPMC HPMC HPMC HPMC HPMC HPMC HPMC HPMC

Example 4: PK Analysis of Extended Release Oxycodone Compositions (ref.Formulation A and Formulations 2, 3 and 4)

Materials and Methods

This study was an open-label, single-dose, randomized, crossover studyof the pharmacokinetics and bioavailability of oxycodone afteradministration of 40 mg doses of four extended release oxycodonecompositions and oxycodone in solution in fed state to healthyvolunteers.

The study was intended to evaluate the in vivo performance of severalvariants of Reference Formulation A (primarily HEC, IPM, and SAIB) andthe effect of changing the capsule shell from gelatin to hydroxylpropylmethylcellulose (HPMC).

The study was conducted as an open-label, single-dose, 5-way crossoverstudy in 16 healthy adult volunteers. The treatments (ReferenceFormulation A, three modified oxycodone compositions Formulation 1(Reference Formulation A in HPMC), Formulation 2 and Formulation 3, andan oral oxycodone solution; see Table 3) were administered undernaltrexone blockade and following ingestion of an intermediate-sizebreakfast (˜450 calories). The primary objective was to estimate thepharmacokinetics and bioavailability of oxycodone following single oral40 mg doses of three modified compositions relative to the ReferenceFormulation A. The oral solution was included for the purpose ofexploratory in vitro in vivo correlation analysis.

TABLE 3 Reference Formulation A Gelatin capsule shell, (without BHT) 40mg oxycodone Reference Formulation 1 HPMC capsule shell, Test (Reference40 mg oxycodone Formulation A in HPMC) Formulation 2 HPMC capsule shellwithout Test HEC, 40 mg oxycodone Formulation 3 HPMC capsule shell withTest 50% reduced IPM content and increase in SAIB, 40 mg oxycodone Oralsolution Oral solution of Oral solution oxycodone 40 mgResults

The mean plasma oxycodone concentration profiles are shown in FIG. 3.The mean (CV %) values for the oxycodone PK parameters are summarized inTable 4, below, along with the geometric mean ratios and 90% confidenceintervals for each test composition relative to the ReferenceFormulation A. Compared with the rapid oral absorption characteristicsof the oral solution, Reference Formulation A and the 3 modifiedoxycodone compositions demonstrated drug delivery characteristicsconsistent with extended release of the Reference Formulation A. Theresults demonstrated that changing the capsule shell from gelatin toHPMC did not significantly affect the controlled-release characteristicsof the composition based on the geometric mean ratios for C_(max) andAUC. In contrast, the C_(max) and AUC values for the test Formulations 2and 3, which involved significant changes in excipients—either a removalof HEC (Formulation 2) or a 50% reduction in IPM and correspondingincrease in SAIB—the key hydrophobic constituent of ReferenceFormulation A—(Formulation 3), were generally slightly lower on C_(max)(by approx. 15-20%) than those for Reference Formulation A even thoughtheir controlled-release characteristics were retained as compared withthe oral solution (Table 4). However, AUC point estimates were similarto the Reference Formulation A (within approx. 90-100% of ReferenceFormulation A).

TABLE 4 PK Summary Reference Formulation A Parameter (without BHT)Formulation 1 Formulation 2 Formulation 3 Oral Solution (Units) (N = 14)(N = 16) (N = 14) (N = 13) (N = 14) C_(max) (ng/mL) 62.8 (34)  58.5(26)  51.1 (26)  55.0 (36)  116 (20) T_(max) (hr)    5.0 (2.0-6.0)   6.0 (2.0-6.0)    6.0 (4.0-6.1)    4.0 (2.0-8.0)    2.0 (0.5-6.0)AUC_(last) 752 (12) 745 (21) 691 (27) 676 (24) 817 (17) (ng*hr/mL)AUC_(inf) 772 (13) 764 (22) 712 (28) 708 (23) 818 (17) (ng*hr/mL)t_(1/2) (hr)  7.88 (3.01)  8.01 (3.03)  8.56 (2.66)  9.72 (3.86)  5.83(0.58) BA Assessment Bioavailability (%) Relative to Formulation A [90%Confidence Interval] Parameter Formulation 1 Formulation 2 Formulation 3C_(max) 92.8 80.1 87.5 [77.5, 111.0] [66.5, 96.4] [72.5, 105.6]AUC_(inf) 100.5 92.1 91.6 [91.4, 110.5] [83.5, 101.5] [83.0, 101.1]Geometric mean (% CV) for AUC, C_(max); median (range) for T_(max);arithmetic mean (±SD) for t_(1/2).

Example 5: PK and BA Analysis of Extended Release Oxycodone Compositions(ref. Formulation A and Formulations 4, 5, 6, 7 and 5^(A))

Materials and Methods

This study was intended to evaluate the in vivo performance of severalvariants of Reference Formulation A (primarily changes in the relativeamounts of TA and IPM). In addition, Formulation 7—a slight variant ofFormulation 5, differing only with respect to silicon dioxide (CSD)content—was evaluated as an add-on treatment arm to complete the study.Likewise, the pharmacokinetics and dose proportionality of a 5 mg doseof the 40 mg test Formulation 5 after the initial 4-way crossoverportion of the study with Reference Formulation A, 4, 5, and 6 wascompleted. HPMC capsule shells were used in each modified oxycodonecomposition, while gelatin capsule shells were used for ReferenceFormulation A.

This was an open-label, single-dose, randomized, crossover study inhealthy adult (18-55 years) male and female volunteers. Twenty (N=20)subjects who met study eligibility criteria were enrolled. The studyoccurred in three parts. In Part I, three modified oxycodonecompositions (Formulations 4, 5, and 6) were compared with ReferenceFormulation A using a standard single-dose, 4-period, crossover studydesign, with at least a one-week washout period between doses. Followingthe completion of Part I, the pharmacokinetic results were reviewed andthe test composition that had the PK profile closest to that ofReference Formulation A was selected for Part II (Period 5) to evaluatedose proportionality of the 5 mg strength. After completion of Part II,the protocol was amended to estimate the relative bioavailability of anadditional composition (Formulation 7), as part of an add-on,fixed-sequence study design (Part III, Period 6), in the same studypopulation.

All compositions were administered under naltrexone blockade andfollowing ingestion of an intermediate-size breakfast (˜450 calories).

Results

The mean plasma oxycodone concentration profiles and summary statisticsfor oxycodone PK parameters following single oral doses of eachcomposition tested in this study are shown in FIG. 4 and Table 5,respectively. The initial study results indicated that Formulation 5 hadthe oxycodone PK and BA characteristics closest to Reference FormulationA with respect to in vivo performance. Therefore, Formulation 5 wasselected to establish the dose-proportionality relationship between the5 mg and 40 mg dosage strengths. The statistical analysis results forrelative bioavailability of Formulations 4, 5, 6, and 7 vs. ReferenceFormulation A, and for the dose proportionality relationship with the 5mg dosage form (Formulation 5) are also shown in Table 5.

TABLE 5 PK Summary Reference Formulation A Parameter (without BHT)Formulation 4 Formulation 5 Formulation 6 Formulation 7 Formulation5^(a) (Units) (N = 19) (N = 20) (N = 20) (N = 20) (N = 18) (N = 19) Dose40 mg 40 mg 40 mg 40 mg 40 mg 5 mg C_(max) (ng/mL) 41.3 (41) 32.6 (29)46.4 (39) 52.1 (35) 35.5 (37) 4.88 (29) T_(max) (hr) 4.0 (2.0-8.0) 6.0(4.0-12.0) 6.0 (4.0-8.0) 4.0 (2.0-12.0) 6.0 (4.0-14.0) 4.0 (2.0-8.0)AUC_(last) 581 (23) 523 (25) 592 (22) 587 (19) 571 (19) 62.8 (27) (ng *hr/mL) AUC_(inf) 605 (23) 544 (24) 600 (22) 596 (19) 580 (19) 66.4 (26)(ng * hr/mL) t_(1/2) (hr) 9.20 + 2.91 8.95 + 2.83 6.70 + 1.14 7.07 +1.81 6.36 + 1.74 8.65 + 2.74 BA Assessment Parameter Bioavailability (%)Relative to Formulation A [90% Confidence Interval] Formulation 4 5 6 75^(b) Dose 40 mg 40 mg 40 mg 40 mg 5 mg C_(max) 79.5 [68.6, 92.1] 113.3[97.7, 131.3] 127.2 [109.7, 147.3] 85.1 [73.4, 98.6]  84.1 [72.0, 98.2]AUC_(inf) 89.2 [84.4, 94.2]  98.4 [93.1, 104.0] 97.8 [92.6, 103.3] 93.5[87.2, 100.2] 88.7 [81.1, 97.1] Geometric mean (% CV) for AUC, C_(max);median (range) for T_(max); arithmetic mean (±SD) for t_(1/2).^(a)similar in composition to Formulation 5 except for drug content (5mg) ^(b)dose-normalized comparison relative to Formulation 5

The above results indicate that each modified composition tested behavedlike a controlled-release composition similar to the ReferenceFormulation A, with median T_(max) values ranging between 4 and 6 hours(compared with 1-hour when oxycodone is administered as animmediate-release composition; data not shown). The study also revealedthat changing the ratio of certain excipients in the ReferenceFormulation A can result in varying degrees of changes in oxycodoneC_(max) (approx. −21% to +27%), with similar extent of bioavailability.

Of the three compositions tested, Formulation 5, with a C_(max) ratio ofapproximately 113% and 90% CI of 97.7-131.3%, was considered closest tothe Reference Formulation A and, therefore, was selected for evaluationat the 5 mg dose in Part II to assess the dose proportionalityrelationship. In general, there was a dose-related increase in oxycodoneC_(max) (4.9 ng/mL vs. 46.4 ng/mL) and AUC_(inf) (66.4 ng·h/mL vs. 600ng·h/mL) as shown in Table 5.

After completing the PK evaluations for Reference Formulation A andFormulations 4, 5, and 6, an additional treatment arm was added to thestudy to determine the bioavailability of Formulation 7 (a slightvariant of Formulation 5 with increased CSD content). The results ofthis study suggest that increasing CSD in the composition from 1.9% to3.9% can potentially decrease C_(max) by approximately 15% relative toReference Formulation A, without substantially impacting the extent ofabsorption.

Example 6: PK Analysis of Extended Release Oxycodone Compositions (ref.Formulation A and Formulations 8 and 9)

Materials and Methods

This study was an open-label, single-dose, randomized crossover study toevaluate the pharmacokinetics and relative bioavailability of oxycodonefollowing oral administration of 40 mg doses.

The test compositions in this study were prepared based on the resultsfrom Example 5 above, which suggested that making intermediateadjustments to the CSD content—i.e., relative to the 1.9% CSD content inFormulation 5 and the 3.9% CSD content in Formulation 7—had thepotential to provide in vivo drug delivery characteristics of themodified oxycodone composition similar to Reference Formulation A. Thisstudy was designed to evaluate the PK and bioavailability of single oral40 mg doses of modified compositions (Formulations 8 and 9) comparedwith Reference Formulation A.

This was a randomized, open-label, single-dose, 4-treatment, 4-period,crossover study in healthy volunteers. Eighteen (18) subjects aged 18-55years who met inclusion and exclusion criteria were enrolled. Two testmodified oxycodone compositions (i.e., Formulations 8 and 9) and theReference Formulation A were evaluated under fed conditions.

All subjects were to be administered 50 mg of naltrexone HCl by mouth atthe following times: 12 hours before, 30 minutes before, and 12 hoursafter study drug administration to minimize the risk of opioid-relatedAEs. The results are shown below.

Results

The mean plasma oxycodone concentration profiles for oxycodone PKparameters following single oral doses of each composition tested in thestudy are shown in FIG. 5. The summary statistics and statisticalanalysis are given in Table 6, below.

TABLE 6 PK Sumary Reference Parameter Formulation (Units) A (withoutBHT) Formulation 8 Formulation 9 N 18 18 18 C_(max) 31.2 32.8 34.8(ng/mL) (50) (36) (34) T_(max) (hr) 4.0 6.0 (4.0-8.0) (4.0-16.0)(4.0-12.0) AUC_(last) 396 454 447 (ng * (37) (29) (28) hr/mL) AUC_(inf)403 461 453 (ng * (37) (29) (28) hr/mL) t_(1/2) (hr) 7.4 ± 1.7 7.1 ± 1.46.7 ± 1.9 BA Assessment Bioavailability (%) Relative to Formulation A[90% Confidence Interval] Formulation Parameter 8 9 C_(max) 105.2 [87.6,126.3] 111.7 [93.0, 134.1] AUC_(inf)  114.5 [104.6, 125.4]  112.4[102.7, 123.1] Geometric mean (% CV) for AUC, C_(max); median (range)for T_(max); arithmetic mean (±SD) for t_(1/2).

The results of the relative BA study indicate that the two modifiedoxycodone compositions (Formulations 8 and 9) had similar in vivocharacteristics with respect to the rate and extent of oxycodoneabsorption. Each test composition had qualitatively similar PK profilesand bioavailability values, consistent with the desiredcontrolled-release characteristics for a modified oxycodone composition.The C_(max) and AUC ratios for Formulations 8 and 9 were both slightlyhigher compared to Reference Formulation A, which seemed to underperformslightly with respect to oxycodone exposure parameters (C_(max) andAUC). Nevertheless, there was no apparent difference in oxycodonebioavailability (C_(max) or AUC) with the CSD content used in this studyfor Formulation 8 (2.5%) and Formulation 9 (2.9%) based on similar pointestimates and overlapping 90% confidence intervals of Test/Referenceratios. Overall, the preliminary study results indicated thatFormulation 8 and 9 were indistinguishable with respect to PK andbioavailability.

Example 7: Dissolution Performance for Reference Formulation A andFormulations 1-6

Materials and Methods

Dissolution data utilizing the Apparatus 2 method (described below) forReference Formulation A (without BHT) and Formulations 1 to 3 stored upto 12 months and Formulations 4 to 6 stored up to 6 months ataccelerated conditions (40° C./75% RH) and long term storage conditions(25° C./60% RH) are shown in Table 7 and Table 8.

Twelve capsules from each composition were tested with USP Apparatus 2to evaluate the effect on inter-capsule dissolution variability. Therelease rate of oxycodone base was determined using a USP Apparatus 2dissolution tester. Dissolution medium containing 1000 ml 0.1 N HCl with0.5% (w/w) SDS was maintained at 37° C. with 100 rpm paddle speed overthe course of the 24 hour dissolution test. A 20 mesh screen hangingbasket was incorporated to hold the test article and the paddle speedwas set to 100 rpm. The standard sampling time points were 0.5, 2, 3, 6,12 and 24 hours. A 1 mL sample was taken at each time point and assayedusing reverse-phase HPLC at 240 nm wavelength. The mobile phase included0.35% (w/v) SDS/0.7% (v/v) acetic acid/44% (v/v) acetonitrile in water.

Results

The results of the in vitro dissolution analysis are shown in Table 7and Table 8 below.

TABLE 7 Ref. Formulation A Formulation 1 Formulation 2 Formulation 3Storage Check Mean Range Mean Range Mean Range Mean Range ConditionsPoint Hours (%) (%) Hours (%) (%) Hours (%) (%) Hours (%) (%) Initial 02 23 20-31 2 22 18-31 2 24 18-30 2 18 15-27 6 48 42-56 6 43 33-58 6 3828-48 6 34 28-46 24 96  86-104 24 87  68-100 24 59 46-74 24 64 50-80 25°C./60% 3 months 2 22 17-28 2 27 22-30 2 18 15-21 2 17 12-24 RH 6 4437-52 6 48 37-55 6 31 25-37 6 29 23-41 24 94  85-100 24 86 75-94 24 5644-69 24 56 42-71 6 months 2 21 16-28 2 24 19-28 2 21 17-24 2 18 13-25 642 36-54 6 44 36-49 6 39 34-42 6 32 25-43 24 94  80-101 24 93  90-108 2466 58-72 24 60 53-72 12 months  2 21 17-25 2 27 21-30 2 25 19-32 2 2016-25 6 45 38-53 6 54 44-63 6 40 30-52 6 35 29-45 24 87 79-92 24 9284-97 24 60 45-75 24 64 51-72 40° C./75% 1 month  2 18 14-28 2 21 17-25Not Evaluated RH 6 37 29-50 6 44 36-52 24 81 71-92 24 84 78-92 3 months2 14 11-16 2 22 19-26 6 31 27-36 6 47 41-54 24 81 68-90 24 96  90-102 6months 2 16 12-24 2 23 19-30 6 37 29-48 6 51 45-58 24 87 75-98 24 98 95-103

TABLE 8 Formulation 4 Formulation 5 Formulation 6 Storage Check MeanRange Mean Range Mean Range Conditions Point Hours (%) (%) Hours (%) (%)Hours (%) (%) Initial 0 2 25 18-31 2 29 23-35 2 28 24-32 6 48 37-59 6 6153-74 6 55 50-63 24 85 72-95 24 98  93-103 24 95  90-102 25° C./60% 3months 2 24 19-33 2 29 24-37 2 29 26-38 RH 6 47 34-62 6 63 56-74 6 6053-72 24 86 57-98 24 103  95-100 24 103  95-106 6 months 2 25 18-29 2 2822-34 2 30 26-37 6 51 36-63 6 60 50-74 6 60 53-71 24 85 66-97 24 94 90-100 24 96  90-102 40° C./75% 1 month  2 21 18-26 2 22 18-28 2 2826-32 RH 6 45 34-54 6 54 45-63 6 57 51-65 24 89 74-99 24 100  95-106 2488 85-91 3 months 2 23 18-29 2 27 23-32 2 32 26-37 6 45 29-58 6 60 52-686 64 55-75 24 84 61-95 24 100  93-106 24 103  99-110 6 months 2 25 21-322 32 28-37 2 33 27-41 6 52 42-67 6 63 55-69 6 63 46-76 24 86  74-100 2495 91-98 24 98  93-102

All compositions showed extended release. Formulations 2 and 3 showedincomplete dissolution release relative to the other compositions. Nosignificant change was observed in mean dissolution performance forFormulations 1, 4, 5 and 6 when stored up to 6 months at accelerated orlong term storage conditions when compared to initial data. Theinter-capsule dissolution variability was not significantly reduced forFormulations 1, 4, 5 and 6 when compared to Reference Formulation A.

The observation that the mean dissolution performance for Formulations1, 4, 5 and 6 following storage for varying time periods and conditionsdid not significantly change supports the conclusion that adjusting thecomposition components as indicated for Formulations 4, 5 and 6 andchanging the capsule shell to HPMC may decrease or eliminate the timedependent changes in drug release performance seen for ReferenceFormulation A.

Example 8: Preparation and Analysis of Extended Release OxycodoneCompositions (Reference Formulation A and Formulations 10-13)

Additional compositions (Formulations 10-13) with varying concentrationsof isopropyl myristate (IPM) and silicon dioxide (SiO₂) were preparedand compared with Reference Formulation A (with BHT) to determine theeffect of these components on inter-capsule dissolution variability andrheology as indicated below.

Materials and Methods

The compositions were prepared as described above for Example 3 toprovide the compositions indicated in Table 9 (below).

TABLE 9 (mg) Vehicle Composition (% w/w) Oxy- ID SAIB TA IPM CAB HECSiO₂ BHT codone Reference 43 29 15 5 6 2 0.02 40 Formulation AFormulation 47 32 8 5 6 2 0.02 40 10 Formulation 52 35 0 5 6 2 0.02 4011 Formulation 44 29 15 5 6 1 0.02 40 12 Formulation 44 30 15 5 6 0 0.0240 13

Dissolution Testing

Four capsules from each composition were tested with USP Apparatus 2 toevaluate the effect on inter-capsule dissolution variability. Therelease rate of oxycodone base was determined using a USP Apparatus 2dissolution tester. Dissolution medium containing 1000 ml 0.1 N HCl with0.5% (w/w) SDS was maintained at 37° C. over the course of the 24 hourdissolution test. A 20 mesh screen hanging basket was incorporated tohold the test article and the paddle speed was set to 100 rpm. Thestandard sampling time points were 0.5, 2, 3, 6, 12, 18 and 24 hours. A1 mL sample was taken at each time point and assayed using reverse-phaseHPLC at 240 nm wavelength. The mobile phase included 0.35% (w/v)SDS/0.7% (v/v) acetic acid/44% (v/v) acetonitrile in water.

Rheology Testing

Samples of the above compositions (Table 9) were analyzed forrheological properties using an Anton Paar MCR301 Rheometer. The sampleswere exposed to increasing dynamic strain (0.1 to 100%) at a constantangular frequency (10 s⁻¹) at 25° C.

Results

Dissolution Testing Results

The results of the dissolution experiments are shown in FIGS. 6 and 7.The in vitro dissolution results showed a reduction in the inter-capsuledissolution variability with a reduction in the concentration of IPM inthe composition (see FIG. 6, Panels A-C). Sample variability wassignificant when the level of SiO₂ in the composition was less than 2%as shown in FIG. 7, Panels A-C. The effects of adjusting theconcentration of IPM and SiO₂ on the dissolution profiles of thecompositions are shown in FIG. 8, Panels A and B, respectively, whereinthe 0% IPM composition exhibited increased mean release at later timepoints, and the 0% SiO₂ composition exhibited increased mean release atearlier time points.

Rheology Testing Results

Table 10 (below) summarizes the viscoelastic outputs at the linearviscoelastic range for the rheology analysis.

TABLE 10 Storage Loss Damp- Complex Modulus Modulus ing Viscosity (G′)(G″) Factor ID Description (Pa · s) (Pa) (Pa) (G″/G′) Reference (15%IPM, 53.3 239 476 1.99 Formulation 2% SiO₂) A Formulation (8% IPM) 90.3473 769 1.63 10 Formulation (0% IPM) 158 993 1230 1.24 11 Formulation(1% SiO₂) 51.8 229 464 2.02 12 Formulation (0% SiO₂) 41.1 173 373 2.1613

Compositions with lower % IPM (as compared to Reference Formulation A)had higher complex viscosity and higher elastic property (higher G′ andlower G″/G′). Without intending to be bound by any particular theory,these properties may have resulted in the observed decrease ininter-capsule dissolution variability. Compositions with lowerconcentrations of SiO₂ had lower viscosity and lower elastic property(lower G′ and high G″/G′) similar to Reference Formulation A. Withoutintending to be bound by any particular theory, the lower elasticproperty could relate to an increase in the deformation of thecomposition structure due to hydrodynamic forces in the dissolutionmedia.

Example 9: Preparation and Analysis of Extended Release OxycodoneCompositions (Formulations 14 and 15)

Additional compositions (Formulations 14 and 15) and Formulation 1(Reference Formulation A without BHT in HPMC capsule) were prepared andcharacterized with respect to inter-capsule dissolution variability,rheology and abuse deterrence characteristics as indicated below.

Materials and Methods

The compositions were prepared to provide the compositions indicated inTable 11 (below). Composition components were blended and individualcompositions were encapsulated as described above, with the exceptionthat HPMC capsules were used in place of gelatin capsules.

TABLE 11 Composition (% w/w) Formulation 1 Formulation 14 Formulation 15SAIB 40.99 40.42 39.85 TA 27.32 26.94 26.56 IPM 14.23 14.23 14.23 CAB4.74 4.74 4.74 HEC 5.69 5.69 5.69 Colloidal SiO₂ 1.90 2.85 3.79Micronized 5.13 5.13 5.13 oxycodone base Capsule shell HPMC HPMC HPMC

Dissolution Testing

Six capsules from each composition lot were tested according to thetesting conditions discussed above to evaluate the effect on meanrelease and inter-capsule dissolution variability.

Rheology Testing

Triplicate samples for each composition were subjected to rheologytesting as discussed above.

Abuse Deterrence

Four capsules from each composition were tested for abuse deterrencecharacteristics. The release rate of oxycodone base was determined usingan isocratic HPLC method at defined time points. The capsules weresubjected to 60 mL of acidified 80-proof ethanol with vigorous shaking.Each capsule was placed in a wide mouth round jar containing 36 mL of0.1 N HCl and 24 mL 200-proof of ethanol. The sample jar was placed in ashaking incubator maintained at 25° C. with 240 rpm shaking speed overthe course of the 3 hour extraction test. The sampling time points were0.5, 1, and 3 hours. A 1 mL sample was taken at each time point andassayed using reverse-phase HPLC at 240 nm wavelength. The mobile phaseincluded 0.35% (w/v) SDS/0.7% (v/v) acetic acid/44% (v/v) acetonitrilein water.

Results

Dissolution Testing Results

The results of the dissolution experiments are provided in FIG. 9; FIG.10, Panels A-C; and Table 12 (below). The results demonstrate a) areduction in the mean release prior to 12 hours with increasing SiO₂concentration as shown in FIG. 9, and b) a reduction in theinter-capsule dissolution variability with increasing SiO₂ concentrationas shown in FIG. 10, Panels A-C, and Table 12.

TABLE 12 SiO₂ Sam- (% ple Time Point (hrs) ID w/w) No. 0.5 2 3 6 12 1824 Sp* Formula- 1.90 6 Mean 14 42 53 72 88 96 99 7 tion 1 SD 5 8 9 9 8 53 Formula- 2.85 6 Mean 11 30 38 59 81 91 97 5 tion 14 SD 3 5 6 7 6 4 3Formula- 3.79 6 Mean 7 25 34 59 86 96 101 3 tion 15 SD 1 3 4 4 3 3 3 *Spas used herein = Pooled standard deviation which is calculated asprovided below:$s_{p} = \left( \frac{{\left( {n_{1} - 1} \right)s_{1}^{2}} + {\left( {n_{2} - 1} \right)s_{2}^{2}} + {\ldots\mspace{14mu}\left( {n_{k} - 1} \right)s_{k}^{2}}}{n_{1} + n_{2} + {\ldots\mspace{14mu} n_{k}} - k} \right)^{\frac{1}{2}}$wherein, n = sample number and the suffixes 1, 2, . . . k refer to thedifferent series of measurements.

Rheology Testing Results

Table 13 (below) summarizes the results measured at angular frequency of10 s⁻¹. Complex viscosity profiles with angular frequency sweep areshown in FIG. 11.

TABLE 13 Complex Storage Loss Damping SAIB TA IPM SiO₂ Viscosity ModulusModulus Factor ID (% w/w) (% w/w) (% w/w) (% w/w) (Pa · s) (Pa) (G′)(Pa) (G″) (G″/G′) Formulation 40.98 27.32 14.23 1.90 49.53 245.00 474.331.93 1 Formulation 40.41 26.64 14.23 2.85 61.63 311.00 586.67 1.89 14Formulation 39.85 26.56 14.23 3.79 95.50 540.67 874.67 1.62 15

As shown, increasing SiO₂ concentration above about 2% increases complexviscosity which may lead to decreasing matrix deformation and thereforelow inter-capsule variability during dissolution testing. In addition toincrease of the Loss Modulus, it is surprising that the extent ofincrease of Storage Modulus (G′) is even higher which results in lowerdamping factor (G″/G′) for Formulations 14 and 15 as compared withFormulation 1 (Reference Formulation A without BHT in HPMC capsule). Inother word, increasing of SiO₂ does not only increase viscosity but alsoincrease elasticity. Without intending to be bound by any particulartheory, a lower damping factor may indicate a more stable microstructurewhich may lead to more stable dissolution stability.

Abuse Deterrence Results

The % of oxycodone released from each composition at sampling timepoints 0.5, 1, and 3 hours as determined by reverse-phase HPLC isprovided in Table 14 below.

TABLE 14 SiO₂ Sample Time point (hrs) ID (%) # 0.5 1 3 Formulation 1.9 4Mean 22 29 46 1 SD 3 3 5 Formulation 2.85 4 Mean 18 25 41 14 SD 3 4 5Formulation 3.79 4 Mean 17 23 36 15 SD 3 4 7

As shown above, the % release of oxycodone decreased at each time pointwith increased SiO₂ concentration, suggesting an improvement in thisabuse deterrence characteristic with increased SiO₂ in the tested range.

Example 10: One Month Stability Analysis of Extended Release OxycodoneCompositions (Formulations 14 and 15)

Materials and Methods

Formulation 1 (Reference Formulation A without BHT in HPMC capsule) andFormulations 14 and 15 were stored at 25° C./60% RH or 40° C./75% RH fora one-month period of time. Six capsules from each composition lot weretested according to the testing conditions discussed above to evaluatethe effect on mean release and inter-capsule dissolution variability.

Results

The results for Formulation 1 are provided in FIG. 12; FIG. 13, PanelsA-C; and Table 15 below. Mean release is decreased for the storedFormulation 1 capsule samples relative to the T=0 samples as shown inFIG. 12. Inter-capsule variation was similar for the stored Formulation1 samples and the T=0 samples as shown in FIG. 13, Panels A-C and Table15.

TABLE 15 SiO₂ Time Point Storage Sample Time Point (hrs) ID (%) (Months)Condition No. 0.5 2 3 6 12 18 24 Sp Formulation 1.90 0 NA 6 Mean 14 4253 72 88 96 99 7 1 SD 5 8 9 9 8 5 3 1 25° C./60% 6 Mean 10 34 44 62 7988 93 5 RH SD 3 5 6 7 6 5 4 40° C./75% 6 Mean 8 29 37 53 70 79 84 6 RHSD 1 3 3 5 7 8 8

The results for Formulation 14 are provided in FIG. 14; FIG. 15, PanelsA-C; and Table 16 below. Mean release is not significantly changed forthe Formulation 14 samples relative to the T=0 samples as shown in FIG.14. Sample variation was decreased for the Formulation 14 samples storedat 40° C./75% RH relative to the T=0 samples as shown in FIG. 15, PanelsA-C and Table 16.

TABLE 16 SiO₂ Time Point Storage Sample Time Point (hrs) ID (%) (Months)Condition No. 0.5 2 3 6 12 18 24 Sp Formulation 2.85 0 NA 6 Mean 11 3038 59 81 91 97 5 14 SD 3 5 6 7 6 4 3 1 25° C./60% 6 Mean 9 29 38 59 8090 95 8 RH SD 3 7 9 11 10 7 6 40° C./75% 6 Mean 5 21 31 54 78 90 97 2 RHSD 1 2 3 3 2 2 2

The results for Formulation 15 are provided in FIG. 16; FIG. 17, PanelsA-C; and Table 17 below. Mean release is not significantly changed forthe Formulation 15 relative to the T=0 samples as shown in FIG. 16.Sample variation was low and similar for the Formulation 15 samplesstored at 25° C./60% RH and 40° C./75% RH relative to the T=0 samples asshown in FIG. 17, Panels A-C and Table 17.

TABLE 17 SiO₂ Time Point Storage Sample Time Point (hrs) ID (%) (Months)Condition No. 0.5 2 3 6 12 18 24 Sp Formulation 3.79 0 NA 6 Mean 7 25 3459 86 96 101 3 15 SD 1 3 4 4 3 3 3 1 25° C./60% 6 Mean 7 24 32 55 80 9399 2 RH SD 0 1 1 2 3 2 2 40° C./75% 6 Mean 7 25 35 57 80 91 97 2 RH SD 12 2 3 2 2 2

Example 11: Preparation and Analysis of Extended Release OxycodoneCompositions (Formulations 16-18)

Still additional compositions (Formulations 16-18) were prepared andcharacterized with respect to inter-capsule dissolution variability andabuse deterrence characteristics as indicated below.

Materials and Methods

The compositions were prepared to provide the compositions indicated inTable 18 (below). Composition components were blended and individualcompositions were encapsulated in HPMC capsules as described above.

TABLE 18 Low-IPM Compositions Composition (% w/w) Formulation 16Formulation 17 Formulation 18 SAIB 42.93 42.42 41.92 TA 37.14 36.7 36.26IPM 2.47 2.47 2.47 CAB 4.74 4.74 4.74 HEC 5.69 5.69 5.69 Colloidal SiO₂1.90 2.85 3.79 Micronized 5.13 5.13 5.13 oxycodone base Capsule shellHPMC HPMC HPMC

Dissolution Testing

Six capsules from each composition lot were tested according to thetesting conditions discussed above to evaluate the effect oninter-capsule dissolution variability.

Abuse Deterrence

Four capsules from each composition were tested for abuse deterrencecharacteristics. The release rate of oxycodone base was determined usingan isocratic HPLC method at defined time points. The capsules weresubjected to 60 mL of acidified 80-proof ethanol with vigorous shaking.Each capsule was placed in a wide mouth round jar containing 36 mL of0.1 N HCl and 24 mL 200-proof of ethanol. The sample jar was placed in ashaking incubator maintained at 25° C. with 240 rpm shaking speed overthe course of the 3 hour extraction test. The sampling time points were0.5, 1, and 3 hours. A 1 mL sample was taken at each time point andassayed using reverse-phase HPLC at 240 nm wavelength. The mobile phaseincluded 0.35% (w/v) SDS/0.7% (v/v) acetic acid/44% (v/v) acetonitrilein water.

Results

Dissolution Testing Results

The results of the dissolution experiments are provided in FIG. 18; FIG.19, Panels A-C; and Table 19 (below). The results demonstrate a) areduction in the mean release with increasing SiO₂ concentration asshown in FIG. 18, and b) a reduction in the inter-capsule variabilitywith increasing SiO₂ concentration as shown in FIG. 19, Panels A-C, andTable 19.

TABLE 19 SiO₂ Sample Time Point (hrs) ID (% w/w) No. 0.5 2 3 6 12 18 24Sp Formulation 1.90 6 Mean 10 45 61 83 96 99 101 4 16 SD 2 7 6 5 3 2 2Formulation 2.85 6 Mean 7 26 37 59 81 92 97 2 17 SD 1 1 2 3 3 2 2Formulation 3.79 6 Mean N/A 26 36 55 77 90 97 2 18 SD N/A 2 3 3 2 2 1

Abuse Deterrence Results

The % of oxycodone released from each composition at sampling timepoints 0.5, 1, and 3 hours as determined by reverse-phase HPLC isprovided in Table 20 below.

TABLE 20 SiO₂ Sample Time point (hrs) ID (%) # 0.5 1 3 Formulation 1.9 4Mean 26 35 60 16 SD 5 6 8 Formulation 2.85 4 Mean 28 40 64 17 SD 3 3 3Formulation 3.79 4 Mean 14 22 40 18 SD 2 3 4

As shown above, the % release of oxycodone was decreased for the 3.79%SiO₂ composition relative to the 1.9% and 2.85% SiO₂ compositions,suggesting an improvement in this abuse deterrence characteristic at3.79% SiO₂ relative to the 1.9% and 2.85% SiO₂.

Example 12: One Month Stability Analysis of Extended Release OxycodoneCompositions (Formulations 16-18)

Materials and Methods

Formulations 16, 17 and 18 were stored at 25° C./60% RH or 40° C./75% RHfor a one-month period of time. Six capsules from each composition lotwere tested according to the testing conditions discussed above toevaluate the effect on mean release and inter-capsule dissolutionvariability.

Results

The results for Formulation 16 are provided in FIG. 20; FIG. 21, PanelsA-C; and Table 21 below. Mean release decreased with increasing storagetemperature for the stored Formulation 16 samples relative to the T=0samples as shown in FIG. 20. Inter-capsule variation was similar for thestored Formulation 16 samples and the T=0 samples as shown in FIG. 21,Panels A-C and Table 21.

TABLE 21 SiO₂ Time Point Storage Sample Time Point (hrs) ID (% w/w)(Months) Condition No. 0.5 2 3 6 12 18 24 Sp Formulation 1.90 0 NA 6Mean 10 45 61 83 96 99 101 4 16 SD 2 7 6 5 3 2 2 1 25° C./60% 6 Mean 838 49 65 79 85 88 4 RH SD 1 5 4 3 3 4 4 40° C./75% 6 Mean 9 31 40 54 6571 74 3 RH SD 2 3 4 3 4 3 4

The results for Formulation 17 are provided in FIG. 22; FIG. 23, PanelsA-C; and Table 22 below. Mean release is decreased for the Formulation17 samples stored at 40° C./75% RH relative to the T=0 samples as shownin FIG. 22. Sample variation was increased for the Formulation 17samples stored at 25° C./60% RH relative to the T=0 samples as shown inFIG. 23, Panels A-C and Table 22.

TABLE 22 SiO₂ Time Point Storage Sample Time Point (hrs) ID (% w/w)(Months) Condition No. 0.5 2 3 6 12 18 24 Sp Formulation 3 0 NA 6 Mean 726 37 59 81 92 97 2 17 SD 1 1 2 3 3 2 2 1 25° C./60% 6 Mean 7 31 42 6383 93 98 5 RH SD 1 4 5 7 6 4 2 40° C./75% 6 Mean 5 21 29 47 70 84 93 2RH SD 0 1 1 2 3 3 3

The results for Formulation 18 are provided in FIG. 24; FIG. 25, PanelsA-C; and Table 23 below. Mean release is similar for the storedFormulation 18 samples relative to the T=0 samples as shown in FIG. 24.Sample variation was similar for the stored Formulation 18 samples asshown in FIG. 25, Panels A-C and Table 23.

TABLE 23 SiO₂ Time Point Storage Sample Time Point (hrs) ID (% w/w)(Months) Condition No. 0.5 2 3 6 12 18 24 Sp Formulation 3.79 0 NA 6Mean N/A 26 36 55 77 90 97 2 18 SD N/A 2 3 3 2 2 1 1 25° C./60% 6 Mean 523 34 55 78 91 98 4 RH SD 0 3 4 6 5 4 2 40° C./75% 6 Mean 5 22 32 53 7689 97 4 RH SD 0 3 5 6 6 4 3

Example 13: Preparation and Analysis of Extended Release OxycodoneCompositions (Formulations 5, 7, 9, 19 and 20)

Formulations 5, 7, 9, and additional compositions (Formulations 19 and20) were prepared and characterized with respect to inter-capsuledissolution variability and rheology as indicated below.

Materials and Methods

The compositions were prepared to provide the compositions indicated inTable 24 (below). Bulk compositions for Formulations 5 and 7 were mixedto make Formulations 9, 19 and 20. Individual compositions wereencapsulated generally as described above for Example 8, with theexception that HPMC capsules were used in place of gelatin capsules.

TABLE 24 Composition Formu- Formu- Formu- Formu- Formu- (% w/w) lation 5lation 19 lation 9 lation 20 lation 7 Triacetin 39.08 39.08 39.08 39.0839.08 (TA) Isopropyl 2.48 2.48 2.48 2.48 2.48 myristate (IPM) Sucrose40.98 40.48 39.98 39.48 38.98 Acetate Isobutyrate (SAIB) Hydroxyethyl5.69 5.69 5.69 5.69 5.69 cellulose (HEC) Cellulose 4.74 4.74 4.74 4.744.74 acetate butyrate (CAB) Colloidal 1.90 2.40 2.90 3.40 3.90 silicondioxide (Cab- o-sil ®M-5P) Oxycodone 5.13 5.13 5.13 5.13 5.13

Dissolution Testing

Twelve capsules from each composition were tested with USP Apparatus 2to evaluate the effect on inter-capsule dissolution variability. Therelease rate of oxycodone base was determined using a USP Apparatus 2dissolution tester. Dissolution medium containing 1000 ml 0.1 N HCl with0.5% (w/w) SDS was maintained at 37° C. with 100 rpm paddle speed overthe course of the 24 hour dissolution test. A 20 mesh screen hangingbasket was incorporated to hold the test article and the paddle speedwas set to 100 rpm. The standard sampling time points were 0.5, 2, 3, 6,12, 18 and 24 hours. A 1 mL sample was taken at each time point andassayed using reverse-phase HPLC at 240 nm wavelength. The mobile phaseincluded 0.35% (w/v) SDS/0.7% (v/v) acetic acid/44% (v/v) acetonitrilein water.

Rheology Testing

Samples of the above compositions were analyzed for rheologicalproperties using an Anton Paar MCR301 Rheometer equipped with a parallelplate (25 mm diameter) and a gap setting of 1 mm. The samples wereexposed to increasing temperature (20° C. to 80° C.) (at 2° C./min) atconstant (0.5%) strain (oscillation mode) and 1 Hz frequency.Rheological properties for these compositions were compared with thoseof Reference Formulation A and Reference Formulation B, where thevehicle composition of Reference Formulation B was as follows: SAIB(39.98% w/w), Triacetin (29.62% w/w), IPM (16.00% w/w), CAB 380-20BP(5.50% w/w), HEC (5.00% w/w), Cab-O-Sil®M-5P (2.40% w/w), and Gelucire®44/14 (1.50% w/w).

Results

Dissolution Testing Results

The results of the dissolution experiments for the 5 mg oxycodonecompositions are shown in FIG. 26; FIG. 27, Panels A-E; and Table 25below. The in vitro dissolution results indicate an increase in meanrelease at earlier time points with an increase in the concentrationlevel of SiO₂ in the composition (FIG. 26). Formulations 19, 9, 20 and7, with 2.4%, 2.9%, 3.4% and 3.9% SiO₂ respectively, showed decreasedsample variability relative to Formulation 5 (1.9% SiO₂), withFormulation 20 (3.4% SiO₂) showing the least amount of samplevariability (FIG. 27, Panels A-E).

TABLE 25 SiO₂ Sample Time Point (hrs) ID (% w/w) No. 0.5 2 3 6 12 18 24Sp Formulation 1.9 12 Mean 17 46 56 75 91 96 98 5 5 SD 3 7 8 7 5 3 2Formulation 2.4 12 Mean 18 47 60 82 97 100 103 3 19 SD 3 5 5 4 2 1 1Formulation 2.9 12 Mean 15 47 61 84 96 98 98 4 9 SD 2 6 7 5 2 2 2Formulation 3.4 12 Mean 14 43 58 83 98 101 102 2 20 SD 1 3 3 3 2 2 2Formulation 3.9 12 Mean 17 54 68 89 98 100 100 4 7 SD 2 5 5 3 3 3 3

The results of the dissolution experiments for the 40 mg oxycodonecompositions are shown in FIG. 28; FIG. 29, Panels A-E; and Table 26below. The in vitro dissolution results showed a decrease in samplevariability with increasing SiO₂ concentration (FIG. 29, Panels A-E).

TABLE 26 Sam- SiO₂ ple Time Point (hrs) ID (%) No. 0.5 2 3 6 12 18 24 SpFormulation 1.9 12 Mean 8 29 39 58 78 88 94 7 5 SD 2 7 8 10 8 5 3Formulation 2.4 12 Mean 7 23 31 51 73 86 94 4 19 SD 1 4 5 6 5 4 3Formulation 2.9 12 Mean 7 28 39 60 81 93 99 4 9 SD 1 3 4 5 5 3 2Formulation 3.4 12 Mean 6 23 32 52 75 89 97 3 20 SD 1 3 4 5 4 3 2Formulation 3.9 12 Mean 6 30 41 61 82 93 99 3 7 SD 1 3 4 4 3 3 2

Rheology Testing Results

The viscoelastic outputs of the rheology testing experiments areprovided in Tables 27-30 (below) and FIGS. 26-32. As shown in Table 27and FIGS. 30 and 31, the complex viscosity range for the testedcompositions narrows with an increase in temperature. In addition, thereis an increase in complex viscosity with increasing concentration ofSiO₂ for Formulations 5, 7, 9, 19 and 20 as shown in FIGS. 30, 31 and 35(Panel A).

TABLE 27 Complex Viscosity Temp. Formu- Formu- Formu- Formu- Formu- (°C.) lation 5 lation 19 lation 9 lation 20 lation 7 50 17 25 28 32 33 5511 17 19 22 23 61 8 11 13 15 17 65 6 8 10 11 13 70 4 6 7 8 10

TABLE 28 Loss Module (G″) Temp. Formu- Formu- Formu- Formu- Formu- (°C.) lation 5 lation 19 lation 9 lation 20 lation 7 50 103 152 174 196201 55 71 103 118 135 143 61 49 71 82 94 103 65 35 52 60 70 78 70 25 3743 50 58

TABLE 29 Damping Factor (G″/G′) Temp. Formu- Formu- Formu- Formu- Formu-(° C.) lation 5 lation 19 lation 9 lation 20 lation 7 50 5.9 4.7 4.4 3.93.6 55 7.6 5.8 5.3 4.6 4.0 61 9.6 7.0 6.2 5.2 4.2 65 11.5 7.9 6.8 5.54.2 70 13.2 8.5 7.2 5.5 4.0

TABLE 30 Storage Module (G′) Temp. Formu- Formu- Formu- Formu- Formu- (°C.) lation 5 lation 19 lation 9 lation 20 lation 7 50 17 32 40 50 55 559 18 23 30 36 61 5 10 13 19 25 65 3 7 9 13 19 70 2 4 6 9 15

Formulations 19, 9, 20 and 7, with increased concentration of SiO₂ (ascompared to Formulation 5), exhibited higher elastic property (lowerG″/G′) as shown in Tables 27-30 and FIGS. 32-36. Without intending to bebound by any particular theory, this higher elastic property may haveresulted in the lower inter-capsule dissolution variability shown inFIGS. 27 and 29.

Example 14: Stability Analysis of Stored Extended Release OxycodoneCompositions (Formulations 5, 8, 9 and 7)

Formulations 5, 8, 9 and 7 were analyzed following storage for variousperiods of time to determine the effect on drug release andinter-capsule dissolution variability.

Materials and Methods

Formulations 5, 8, 9 and 7 (40 mg oxycodone) were stored at 25° C./60%RH and/or 40° C./75% RH for a total of 6 months, 2 months, 2 months, and3 months respectively. Twelve capsules from each composition lot weretested according to the testing conditions discussed above to evaluatethe effect on mean release and inter-capsule dissolution variability.

Results

The results for Formulation 5 are provided in FIG. 37 and Table 31(below). No significant change in mean release was seen as a result ofstorage up to 6 months for Formulation 5. Formulation 5 testing resultedin a relatively higher level of dissolution sample variation than thatseen for Formulations 9 and 7 (discussed below).

TABLE 31 Time Point Storage Sample Time Point (hrs) (Months) ConditionNo. 0.5 2 6 12 24 Sp 0 N/A 12 Mean 7 29 61 83 98 5 SD 1 4 7 6 3 1 40°C./75% 12 Mean 6 22 54 81 100 3 RH SD 1 3 5 4 3 3 25° C./60% 12 Mean 729 63 86 103 4 RH SD 1 3 5 6 4 40° C./75% 12 Mean 6 27 60 84 100 4 RH SD1 3 6 6 4 6 25° C./60% 12 Mean 7 28 60 81 95 4 RH SD 1 3 6 6 3 40°C./75% 12 Mean 7 32 63 83 95 3 RH SD 1 3 5 4 2

The results for Formulation 8 are provided in FIG. 38 and Table 32below. No significant change in mean release was seen as a result ofstorage up to 2 months for Formulation 8. Formulation 8 testing resultedin a relatively higher level of variation than that seen forFormulations 9 and 7 (discussed below).

TABLE 32 Time Point Storage Sample Time Point (hrs) (Months) ConditionNo. 0.5 2 6 12 24 Sp 0 N/A 12 Mean 6 23 55 77 93 5 SD 1 5 8 6 4 1 40°C./75% 12 Mean 5 24 54 75 91 4 RH SD 1 3 5 5 3 2 25° C./60% 12 Mean 5 2455 77 95 4 RH SD 1 4 6 5 3

The results for Formulation 9 are provided in FIG. 39 and Table 33below. No significant change in mean release was seen as a result ofstorage for up to 2 months for Formulation 9. In addition, Formulation 9showed a relatively low level of inter-capsule dissolution variabilityfollowing storage for a 1 month period.

TABLE 33 Time Point Storage Sample Time Point (hrs) (Months) ConditionNo. 0.5 2 6 12 24 Sp 0 N/A 12 Mean 5 22 53 75 93 2 SD 1 1 2 2 2 1 40°C./75% 12 Mean 5 22 52 74 92 2 RH SD 0 1 2 2 1 2 25° C./60% 12 Mean 5 2353 75 93 1 RH SD 1 1 2 2 1

The results for Formulation 7 are provided in FIG. 40 and Table 34below. No significant change in mean release was seen as a result ofstorage for up to 3 months for Formulation 7. In addition, Formulation 7showed a relatively low level of inter-capsule dissolution variabilityfollowing storage for up to three months.

TABLE 34 Time Point Storage Sample Time Point (hrs) (Months) ConditionNo. 0.5 2 6 12 24 Sp 0 N/A 12 Mean 5 28 59 82 99 2 SD 1 1 2 3 3 1 40°C./75% 12 Mean 6 30 61 83 100 2 RH SD 1 2 2 2 2 3 25° C./60% 12 Mean 632 64 85 98 2 RH SD 0 1 2 3 3 40° C./75% 12 Mean 6 33 65 86 98 2 RH SD 01 2 2 3

The initial T=0 dissolution data from Tables 31-34 was used to calculate% RSD ((SD/mean)×100) for Formulations 5, 8, 9 and 7. The results areprovided below in Table 35. As shown below, Formulations 9 and 7exhibited a % RSD of 5% or less at the 2 and 6 hour time points, whileFormulations 5 exhibited a % RSD of less than 15% at the 2 and 6 hourtime points. Formulation 8 exhibited a % RSD of less than 25% at the 2and 6 hour time points.

TABLE 35 SiO₂ Time point (hrs) ID (%) Sample # 0.5 2 6 12 24 5 1.90 12Mean 7 29 61 83 98 SD 1 4 7 6 3 % RSD 14 14 11 7 3 8 2.50 12 Mean 6 2355 77 93 SD 1 5 8 6 4 % RSD 17 22 15 8 4 9 2.90 12 Mean 5 22 53 75 93 SD1 1 2 2 2 % RSD 20 5 4 3 2 7 3.90 12 Mean 5 28 59 82 99 SD 1 1 2 3 3 %RSD 20 4 3 4 3

Example 15: Preparation and Analysis of Extended Release HydrocodoneCompositions (Formulations 21-26)

Hydrocodone compositions (Formulations 21-26) were prepared andcharacterized with respect to inter-capsule dissolution variability asindicated below.

Materials and Methods

The compositions were prepared to provide the compositions indicated inTable 36 (below). Composition components were blended and individualcompositions were encapsulated in gelatin (Licaps® (GC)) or HPMC (Vcaps®(VC)) capsules as described above.

TABLE 36 Composition (% w/w unless Formu- Formu- Formu- Formu- Formu-Formu- otherwise lation lation lation lation lation lation noted) 21 2223 24 25 26 Hydrocodone 13.64 13.64 13.64 10.00 10.00 10.00 BitartrateSAIB 36.64 35.99 35.61 38.50 37.84 37.45 Triacetin 34.89 34.94 34.9236.67 36.73 36.72 IPM 2.50 2.50 2.50 2.50 2.50 2.50 CAB 4.74 4.74 4.744.74 4.74 4.74 HEC 5.69 5.69 5.69 5.69 5.69 5.69 Cab-O- 1.90 2.50 2.901.90 2.50 2.90 Sil ®M-5P Capsule Shell GC, VC GC, VC GC, VC VC VC VC

Six capsules from each composition lot were tested according to thetesting conditions discussed above to evaluate the effect oninter-capsule dissolution variability.

Results

The results of the dissolution experiments are provided in Table 37(below). A clear trend with respect to inter-capsule dissolutionvariability and SiO₂ concentration was not demonstrated. However,inter-capsule dissolution variability was reduced for each compositionwhen formulated in HPMC capsules as opposed to gelatin capsules.Formulation 23 with 2.9% SiO₂ showed the least amount of inter-capsuledissolution variability.

TABLE 37 SiO₂ Formulation (% Capsule Time point (hrs) ID w/w) ShellSample # 0.5 2 3 6 12 18 24 Sp Formulation 1.90 GC 6 Mean 15 60 75 95101 102 102 6 21 SD 4 9 9 5 4 4 4 VC 6 Mean 13 59 74 95 102 102 102 4 SD2 6 6 3 2 2 2 Formulation 2.50 GC 6 Mean 15 52 66 90 100 102 102 9 22 SD4 12 12 8 7 7 7 VC 6 Mean 11 45 69 94 103 104 105 5 SD 2 5 7 6 4 4 4Formulation 2.90 GC 6 Mean 16 52 67 91 101 103 103 5 23 SD 5 8 7 3 3 3 3VC 6 Mean 10 50 66 92 101 101 102 2 SD 2 4 4 1 2 1 1 Formulation 1.90 VC6 Mean 5 42 58 84 99 100 101 4 24 SD 1 3 4 4 5 4 4 Formulation 2.50 VC 6Mean 9 45 59 84 100 103 103 4 25 SD 2 5 5 3 3 3 3 Formulation 2.90 VC 6Mean 13 53 66 88 101 103 103 5 26 SD 3 7 7 6 4 4 4

Example 16: Preparation and Analysis of Extended Release AmphetamineCompositions (Formulations 27-30)

Amphetamine compositions (Formulations 27-30) were prepared andcharacterized with respect to inter-capsule dissolution variability asindicated below.

Materials and Methods

The compositions were prepared to provide the compositions indicated inTable 38 (below). Composition components were blended and individualcompositions were encapsulated in HPMC (Vcaps® (VC)) capsules asdescribed above.

Dissolution experiments were performed using 2-phase medium in a USPApparatus 2. The capsules were placed in stainless steel (316SS) wirespiral capsule sinkers for dissolution testing. The dissolutionparameters were as follows:

Dissolution medium: 750 ml 0.1N HCl for the first 2 hours, add 200 ml0.19M phosphate buffer to achieve a final pH of 6.0; Paddle speed: 50rpm; Vessel temperature: 37 C. Sampling time points: 0.25, 0.5, 1, 1.5,2, 3, 6, 9, 12 and 24 hours. Sampling volume: 1 mL.

The HPLC parameters were as follows: Mobile phase A: 5 mM1-Decanesulfonic acid, sodium salt, 5 mM sodium phosphate monobasic, pH2.5; Mobile phase B: 100% acetonitrile; Mobile phase: 67% Mobile phase Aand 33% Mobile phase B; 210 nm wavelength.

TABLE 38 Composition Formu- Formu- Formu- Formu- (% w/w) lation 27lation 28 lation 29 lation 30 D-Amphetamine 10.00 10.00 10.00 10.00Sulfate SAIB 38.50 37.84 37.45 36.59 Triacetin 36.67 36.73 36.72 36.59IPM 2.50 2.50 2.50 2.50 CAB 4.74 4.74 4.74 4.74 HEC 5.69 5.69 5.69 5.69Cab-O-Sil ®M-5P 1.90 2.50 2.90 3.90 Capsule Shell VC VC VC VCResults

The results of the dissolution experiments are provided in Table 39(below).

TABLE 39 Formulation SiO₂ Capsule Time point (hrs) ID (%) Shell Sample #0.25 0.5 1 1.5 2 3 6 9 12 24 Sp Formulation 1.90 VC 6 Mean 4 11 22 30 3850 76 94 100 106 4 27 SD 0 1 2 2 3 4 4 5 2 3 Formulation 2.50 VC 6 Mean4 12 23 33 41 52 79 93 100 104 3 28 SD 1 1 1 1 1 2 2 2 2 5 Formulation2.90 VC 6 Mean 4 12 25 36 46 58 84 99 105 108 2 29 SD 0 1 0 1 1 1 1 1 22 Formulation 3.90 VC 6 Mean 5 14 28 39 48 61 88 101 106 108 5 30 SD 1 23 3 4 4 4 3 4 4

Example 17: Preparation and Analysis of Extended Release MethylphenidateCompositions (Formulations 31-34)

Methylphenidate compositions (Formulations 31-34) were prepared andcharacterized with respect to inter-capsule dissolution variability asindicated below.

Materials and Methods

The compositions were prepared to provide the compositions indicated inTable 40 (below). Composition components were blended and individualcompositions were encapsulated within HPMC (Vcaps® (VC)) capsules asdescribed above.

Dissolution experiments were performed using 2-phase medium in a USPApparatus 2. The capsules were placed in stainless steel (316SS) wirespiral capsule sinkers for dissolution testing. The dissolutionparameters were as follows:

Dissolution medium: 750 ml 0.1N HCl for the first 2 hours, add 200 ml0.19M phosphate buffer to achieve a final pH of 6.0; Paddle speed: 50rpm; Vessel temperature: 37 C. Sampling time points: 0.25, 0.5, 1, 1.5,2, 3, 6, 9, 12 and 24 hours. Sampling volume: 1 mL.

The HPLC parameters were as follows: Mobile phase A: 5 mM1-Decanesulfonic acid, sodium salt, 5 mM sodium phosphate monobasic, pH2.5; Mobile phase B: 100% acetonitrile; Mobile phase: 71% Mobile phase Aand 29% Mobile phase B; 210 nm wavelength.

TABLE 40 Composition Formu- Formu- Formu- Formu- (% w/w) lation 31lation 32 lation 33 lation 34 Methylphenidate 20.00 20.00 20.00 20.00HCl SAIB 33.38 32.76 32.40 31.59 Triacetin 31.79 31.81 31.77 31.59 IPM2.50 2.50 2.50 2.50 CAB 4.74 4.74 4.74 4.74 HEC 5.69 5.69 5.69 5.69Cab-O-Sil ®M-5P 1.90 2.50 2.90 3.90 Capsule Shell VC VC VC VCResults

The results of the dissolution experiments are provided in Table 41(below).

TABLE 41 Formulation SiO₂ Capsule Time point (hrs) ID (%) Shell Sample #0.25 0.5 1 1.5 2 3 6 9 12 24 Sp Formulation 1.90 VC 6 Mean 3 11 24 34 4255 82 95 100 103 2 31 SD 1 1 1 2 2 2 2 2 2 2 Formulation 2.50 VC 6 Mean4 12 27 38 48 61 89 100 102 104 2 32 SD 1 1 2 2 2 2 2 1 1 1 Formulation2.90 VC 6 Mean 4 14 29 41 51 65 92 101 104 105 2 33 SD 1 2 1 1 1 1 1 2 23 Formulation 3.90 VC 6 Mean 4 14 30 42 52 66 92 99 102 103 2 34 SD 1 22 2 1 1 2 2 2 2

Example 18: Preparation and Analysis of Extended Release HydromorphoneHCL Compositions (Formulations 35-45)

Hydromorphone compositions were prepared and characterized with respectto dissolution profile, inter-capsule dissolution variability, and abusedeterrence characteristics as indicated below.

Materials and Methods

The compositions were prepared to provide the compositions indicated inTable 42 (below). Composition component amounts are % w/w relative tothe total weight of the formulation including hydromorphone HCl prior toencapsulation unless otherwise noted.

The formulations were prepared in 100 g scale. The temperature of theformulation compounding was maintained at 80° C.±5° C. and the mixingspeed was maintained at 1500 rpm. Sucrose Acetate Isobutyrate (SAIB) wastransferred into a glass container. Sieved cellulose acetate butyrate(CAB) was added to the bottle while mixing. After mixing forapproximately 5 minutes, triacetin (TA) was added and mixed until themass became clear. Butylated hydroxytoluene (BHT) was dissolved first inisopropyl myristate (IPM) and added into bottle with mixing.Hydroxyethyl cellulose (HEC) was added into the bottle and mixed well.In addition, formulations containing Labrafil M2125CS and/or sodiumdodecyl sulfate (SDS) were added here and mixed well. Finally colliodalsilicon dioxide (Cab-O-Sil®M-5P) was added into the bottle and weremixed to complete the formulation. Hydromorphone HCl was added intoplacebo formulation and dispersed well. Active formulations were thenfilled into size 0 gelatin capsules.

For all formulations BHT was included at a concentration of 0.02% w/wrelative to the total weight of the placebo, i.e., the total weight ofall components except hydromorphone HCl. The concentration of BHT is nottaken into account in the % w/w calculations provided in Table 42 below.

TABLE 42 Formulation SAIB/TA Hydromorphone ID (ratio) SAIB Triacetin IPMCAB SDS Labrafil HCl HEC SiO2 35 1.8 41.78 23.21 16.95 3.77 0.94 2.835.82 1.88 2.83 36 1.2 34.60 28.83 10.72 3.57 0.89 2.68 10.67 7.15 0.8937* 1.8 41.78 23.21 11.30 7.53 0 0 5.82 7.53 2.83 38 1.2 32.65 27.2116.08 3.57 0 0.00 10.67 7.15 2.68 39* 1.2 33.39 27.83 11.30 7.53 0.942.83 5.82 7.53 2.83 40 1.8 43.64 24.25 10.72 3.57 0 2.68 10.67 1.79 2.6841* 1.2 33.13 27.61 16.08 7.15 0.89 0 10.67 1.79 2.68 42 1.2 41.61 34.6811.30 3.77 0 0.00 5.82 1.88 0.94 43* 1.6 41.15 25.72 11.30 5.65 0 0.005.82 7.53 2.83 44* 1.2 34.42 28.68 11.30 5.65 0.94 2.83 5.82 7.53 2.8345 1.2 34.11 28.42 16.08 5.36 0.89 0.00 10.67 1.79 2.68 *finalformulation was not prepared due to high viscosity

Dissolution Testing

Dissolution experiments were performed using 2-phase medium in a USPApparatus 2. The capsules were placed in stainless steel (316SS) wirespiral capsule sinkers for dissolution testing. The dissolutionparameters were as follows:

Dissolution medium: 750 ml 0.1N HCl for the first 2 hours, add 250 ml0.2 M phosphate buffer to achieve a final pH of 6.8; Paddle speed: 100rpm; Vessel temperature: 37 C. Sampling time points: 0.25, 0.5, 1, 2, 3,6, 10, 12, 18 and 24 hours. Sampling volume: 1 mL.

The HPLC parameters were as follows: Mobile phase A: 0.5% sodium dodecylsulfate 1% glacial acetic acid, 20% acetonitrile; Mobile phase B: 100%acetonitrile; Mobile phase: 65% Mobile phase A and 35% Mobile phase B;240 nm wavelength. Capsule number=2-4 capsules per testing.

Abuse Deterrence

Capsules from each composition were tested for abuse deterrencecharacteristics. The release rate of hydromorphone HCl was determinedusing an isocratic HPLC method at defined time points. The capsules weresubjected to 60 mL of acidified 80-proof ethanol with vigorous shaking.Each capsule was placed in a wide mouth round jar containing 36 mL of0.1 N HCl and 24 mL 200-proof ethanol. The sample jar was placed in ashaking incubator maintained at 25° C. with 240 rpm shaking speed overthe course of the 3 hour extraction test. The sampling time points were0.5, 1, 2 and 3 hours. A 1 mL sample was taken at each time point andassayed using reverse-phase HPLC at 240 nm wavelength. The mobile phaseincluded 0.35% (w/v) SDS/0.7% (v/v) acetic acid/44% (v/v) acetonitrilein water.

Results

Dissolution Testing Results

The results of the dissolution experiments are provided in FIG. 41 andTables 43-44 below.

TABLE 43 HMH Cumulative Drug Released (%) Dissolution (mg) 0.25 hr 0.5hr 1 hr 2 hr 3 hr 6 hr 10 hr 12 hr 18 hr 24 hr Formulation 35 #1 29.000.44 0.66 0.88 1.35 1.62 2.59 3.45 4.10 5.25 6.62 #2 28.80 0.44 0.580.85 1.32 1.64 2.53 3.64 4.28 5.57 7.78 #3 28.43 0.77 0.95 1.33 1.852.12 3.04 4.21 4.91 6.30 7.56 #4 28.95 0.89 1.05 1.45 2.00 2.40 3.404.83 5.41 7.38 9.18 Average 28.80 0.6 0.8 1.1 1.6 1.9 2.9 4.0 4.7 6.17.8 Std Dev 0.26 0.2 0.2 0.3 0.3 0.4 0.4 0.6 0.6 0.9 1.1 % RSD 0.89 36.228.0 26.9 21.5 19.6 14.1 15.4 12.9 15.5 13.6 Formulation 36 #1 28.003.28 5.32 10.02 20.39 29.00 47.70 62.22 67.60 80.14 88.41 #2 28.29 4.247.11 13.27 26.37 36.62 56.93 74.39 80.92 94.43 100.02 #3 28.95 3.41 5.529.87 20.30 28.18 45.12 59.34 65.09 79.34 88.73 #4 28.19 2.70 4.15 7.8616.46 24.46 42.29 57.86 64.18 79.15 89.89 Average 28.36 3.4 5.5 10.320.9 29.6 48.0 63.5 69.4 83.3 91.8 Std Dev 0.41 0.6 1.2 2.2 4.1 5.1 6.37.5 7.8 7.5 5.5 % RSD 1.45 18.6 22.0 21.8 19.6 17.2 13.2 11.8 11.2 9.06.0 Formulation 38 #1 28.49 1.27 1.85 2.95 5.38 7.40 16.07 29.88 36.1251.86 64.22 #2 28.02 1.20 1.80 3.06 5.83 8.28 17.56 31.03 37.41 53.8567.02 #3 27.17 1.19 1.66 2.83 5.55 8.10 18.67 35.00 42.26 59.55 72.15 #427.74 1.00 1.62 2.75 5.35 7.62 16.19 29.23 35.11 50.34 62.61 Average27.85 1.2 1.7 2.9 5.5 7.9 17.1 31.3 37.7 53.9 66.5 Std Dev 0.55 0.1 0.10.1 0.2 0.4 1.2 2.6 3.2 4.0 4.2 % RSD 1.99 9.7 6.1 4.6 4.0 5.2 7.2 8.38.4 7.5 6.3 Formulation 40 #1 28.99 0.47 0.63 0.82 1.21 1.81 3.02 4.965.94 9.47 13.25 #2 28.61 0.89 1.15 1.52 2.23 2.82 5.06 8.36 10.33 16.2822.85 #3 28.80 0.55 0.67 0.88 1.33 1.78 3.19 5.42 6.81 10.95 14.97 #428.70 0.89 1.01 1.40 2.14 2.81 4.64 7.21 8.77 13.54 18.32 Average 28.780.7 0.9 1.2 1.7 2.3 4.0 6.5 8.0 12.6 17.3 Std Dev 0.16 0.2 0.3 0.4 0.50.6 1.0 1.6 2.0 3.0 4.2 % RSD 0.56 31.8 29.7 30.7 30.6 25.6 25.7 24.424.8 23.9 24.4 Formulation 42 #1 29.34 3.04 3.58 4.41 5.69 6.71 9.3412.58 13.91 18.05 21.79 #2 29.18 4.73 7.09 10.25 14.34 16.89 21.08 25.2826.97 31.32 35.43 #3 29.23 4.00 6.01 8.64 11.70 13.84 18.14 22.12 23.6327.02 29.94 #4 29.65 2.91 3.72 4.72 6.17 7.38 10.16 13.18 14.33 17.3319.98 Average 29.35 3.7 5.1 7.0 9.5 11.2 14.7 18.3 19.7 23.4 26.8 StdDev 0.21 0.9 1.7 2.9 4.2 5.0 5.8 6.4 6.6 6.9 7.2 % RSD 0.71 23.4 34.041.4 44.7 44.3 39.7 34.9 33.5 29.3 26.9

TABLE 44 Formulation 45 Cumulative Drug Released Hydromorphone (%)Dissolution (mg) 0.25 hr 0.5 hr 1 hr 2 hr 3 hr 6 hr 10 hr 12 hr 18 hr 24hr #1 26.92 2.43 3.28 4.98 8.26 11.01 19.59 31.00 36.15 49.11 59.43 #226.92 1.69 2.73 4.35 7.70 10.51 19.50 30.94 36.08 49.25 59.65 #3 27.861.46 2.24 3.66 6.86 9.58 18.59 30.55 36.06 49.52 59.63 #4 28.33 1.712.48 3.97 7.29 10.17 19.51 32.01 37.51 52.10 63.88 Average 27.51 1.8 2.74.2 7.5 10.3 19.3 31.1 36.4 50.0 60.6 Std Dev 0.71 0.4 0.4 0.6 0.6 0.60.5 0.6 0.7 1.4 2.2 % RSD 2.58 23.2 16.6 13.4 7.9 5.8 2.4 2.0 1.9 2.83.6

Abuse Deterrence Results

The results of the abuse deterrence experiments are provided in FIG. 42and Table 45 below.

TABLE 45 % Accumulative Amount Formulation ID of Drug ReleasedFormulation 35 7.8 Formulation 36 34.1 Formulation 38 26.6 Formulation40 3.9 Formulation 42 39.7 Formulation 45 28.6

Example 19: Preparation and Analysis of Additional Extended ReleaseHydromorphone HCL Compositions (Formulations 46-49)

Additional hydromorphone compositions were prepared and characterizedwith respect to dissolution profile and abuse deterrence characteristicsas indicated below.

Materials and Methods

The compositions were prepared to provide the compositions indicated inTable 46 below. Composition component amounts are % w/w relative to thetotal weight of the formulation including hydromorphone HCl prior toencapsulation unless otherwise noted. The SAIB/triacetin ratio is noted.

The placebo formulations were prepared in 150 g scale. Three stocksolutions, SAIB/TA (1.50), SAIB/TA (1.35) and 0.6% w/v BHT in IPM, wereprepared before the compounding procedure started. A bottle of Gelucire®44/14 was heated at 70° C. and homogenized at 9600 rpm prior to thestarting the preparation. The temperature of the process was maintainedat 60° C.±5° C. SAIB/TA stock solution was added to a jar, and thenpre-heated Gelucire® 44/14 solution was added. The mixture was put intoa water bath, and mixed at 500 rpm. 0.6% BHT/IPM stock solution wastransferred into a vial, the vial was then rinsed with the remaining IPMand added to the formulation. The solution was mixed to ensureuniformity. Cab-O-Sil®M-5P was then added and mixed at 500 rpm. After atleast 30 minutes mixing, the mixture was homogenized for 5 minutes at9600 rpm. Sieved CAB was then added to the mixture and mixed at aninitial speed of 500 rpm followed by mixing at 1500 rpm forapproximately 30 total minutes or until all CAB particles werecompletely dissolved. Then HEC was added last, and mixed at 1500 rpm.Part of the placebo formulation was transferred into a separate bottleand hydromorphone HCl was introduced into the mixture and dispersed wellto make 100 g active formulations. Active formulations were then filledinto size 0 gelatin capsules.

For all formulations BHT was included at a concentration of 0.02% w/wrelative to the total weight of the placebo, i.e., the total weight ofall components except hydromorphone HCl. The concentration of BHT is nottaken into account in the % w/w calculations provided in Table 46 below.

TABLE 46 Formulation Composition Dose (mg)/Fill Cab-O- FormulationWeight (mg)/ Triacetin Sil ®M- Gelucire ® ID Conc. SAIB/TA SAIB (TA) IPMCAB HEC 5P 44/14 46 32/550/5.82% 1.5 39.87 26.58 14.1 5.64 5.64 2.35 047 32/550/5.82% 1.5 39.588 26.392 14.1 5.64 5.64 2.35 0.47 4832/550/5.82% 1.35 38.0654 28.1966 14.1 5.64 5.64 2.35 0.188 4932/550/5.82% 1.35 37.8494 28.0366 14.1 5.64 5.64 2.35 0.564

Dissolution Testing

Dissolution experiments were performed using 2-phase medium in a USPApparatus 2. The capsules were placed in stainless steel (316SS) wirespiral capsule sinkers for dissolution testing. The dissolutionparameters were as follows:

Dissolution medium: 750 ml 0.1N HCl for the first 2 hours; 250 ml 0.2 Mphosphate buffer was added to achieve a final pH of 6.8; Paddle speed:100 rpm; Vessel temperature: 37 C. Sampling time points: 0.25, 0.5, 1,2, 3, 6, 10, 12, 18 and 24 hours. Sampling volume: 1 mL.

The HPLC parameters were as follows: Mobile phase A: 0.5% sodium dodecylsulfate 1% glacial acetic acid, 20% acetonitrile; Mobile phase B: 100%acetonitrile; Mobile phase: 65% Mobile phase A and 35% Mobile phase B;240 nm wavelength. Capsule number=2-4 capsules per testing.

Abuse Deterrence

Capsules from each composition were tested for abuse deterrencecharacteristics. The release rate of hydromorphone HCl was determinedusing an isocratic HPLC method at defined time points. The capsules weresubjected to 60 mL of acidified 80-proof ethanol with vigorous shaking.Each capsule was placed in a wide mouth round jar containing 36 mL of0.1 N HCl and 24 mL 200-proof ethanol. The sample jar was placed in ashaking incubator maintained at 25° C. with 240 rpm shaking speed overthe course of the 3 hour extraction test. The sampling time points were0.5, 1, 2 and 3 hours. A 1 mL sample was taken at each time point andassayed using reverse-phase HPLC at 240 nm wavelength. The mobile phaseincluded 0.35% (w/v) SDS/0.7% (v/v) acetic acid/44% (v/v) acetonitrilein water.

Results

Dissolution Testing and Abuse Deterrence Results

The results of the dissolution and abuse deterrence experiments areprovided in Table 47 below.

TABLE 47 %, Cumulative Formulation Dissolution Results (% CumulativeDrug Released) release after 3 hrs ID 0.25 hr 1.5 hr 1 hr 2 hr 3 hr 6 hr10 hr 12 hr 18 hr 24 hr extraction 46 0.0 0.0 0.4 1.3 1.8 3.1 4.9 6.09.4 13.5 7.0 47 0.0 0.7 1.4 2.7 3.8 7.2 11.8 14.3 21.6 28.9 7.0 48 0.00.0 0.0 0.6 0.8 4.2 6.6 7.9 12.2 16.8 5.0 49 0.0 0.2 1.9 4.0 5.8 12.723.0 27.8 40.4 50.6 8.0

Example 20: Preparation and Analysis of Additional Extended ReleaseHydromorphone HCL Compositions (Formulations 50-81)

Additional hydromorphone compositions were prepared and characterizedwith respect to dissolution profile and abuse deterrence characteristicsas indicated below.

Materials and Methods

The compositions were prepared to provide the compositions indicated inTables 48-50 (below). Component amounts are % w/w relative to the totalweight of the formulation including hydromorphone HCl prior toencapsulation, unless otherwise indicated. The materials and methodsapplicable to the preparation of these formulations are provided in FIG.43. Active formulations were filled into size 2 HPMC capsules.

TABLE 48 Cab-O- Formulation Hydromorphone Sil ®M- Gelucire ® ID HCl SAIBTriacetin CAB IPM HEC 5P 44/14 50 5.82% 45.16% 32.26% 5.65% 1.88% 5.65%2.83% 0.75% 51 5.82% 46.04% 32.88% 5.65% 1.88% 5.65% 1.88% 0.19% 525.82% 42.41% 30.29% 5.65% 7.53% 5.65% 1.88% 0.75% 53 5.82% 45.05% 32.18%5.65% 4.71% 3.77% 2.35% 0.47% 54 5.82% 47.91% 34.22% 5.65% 1.88% 1.88%1.88% 0.75% 55 5.82% 42.19% 30.14% 5.65% 7.53% 5.65% 2.83% 0.19% 565.82% 44.06% 31.47% 5.65% 7.53% 1.88% 2.83% 0.75% 57 5.82% 44.94% 32.10%5.65% 7.53% 1.88% 1.88% 0.19% 58 5.82% 47.69% 34.06% 5.65% 1.88% 1.88%2.83% 0.19%

TABLE 49 Cab-O- Formulation Hydromorphone Sil ®M- Gelucire ® ID HCl SAIBTriacetin CAB IPM HEC 5P 44/14 59 5.82% 41.34% 41.34% 5.65% 1.88% 1.88%1.88% 0.19% 60 5.82% 38.05% 38.05% 5.65% 7.53% 1.88% 2.83% 0.19% 615.82% 38.24% 38.24% 5.65% 7.53% 1.88% 1.88% 0.75% 62 5.82% 38.61% 38.61%5.65% 4.71% 3.77% 2.35% 0.47% 63 5.82% 36.64% 36.64% 5.65% 7.53% 5.65%1.88% 0.19% 64 5.82% 38.99% 38.99% 5.65% 1.88% 5.65% 2.83% 0.19% 655.82% 39.18% 39.18% 5.65% 1.88% 5.65% 1.88% 0.75% 66 5.82% 40.59% 40.59%5.65% 1.88% 1.88% 2.83% 0.75% 67 5.82% 35.88% 35.88% 5.65% 7.53% 5.65%2.83% 0.75%

TABLE 50 Cab-O- Formulation Hydromorphone Sil ®M- Gelucire ® ID HCl SAIBTriacetin CAB IPM HEC 5P 44/14 68 5.82% 42.38% 35.32% 5.65% 4.71% 3.77%1.88% 0.47% 69 5.82% 42.12% 35.10% 5.65% 4.71% 3.77% 2.35% 0.47% 705.82% 42.12% 35.10% 5.65% 4.71% 3.77% 2.35% 0.47% 71 5.82% 41.10% 34.25%5.65% 4.71% 5.65% 2.35% 0.47% 72 5.82% 43.67% 36.39% 5.65% 1.88% 3.77%2.35% 0.47% 73 5.82% 40.58% 33.82% 5.65% 7.53% 3.77% 2.35% 0.47% 745.82% 42.12% 35.10% 5.65% 4.71% 3.77% 2.35% 0.47% 75 5.82% 42.12% 35.10%5.65% 4.71% 3.77% 2.35% 0.47% 76 5.82% 41.87% 34.89% 5.65% 4.71% 3.77%2.83% 0.47% 77 5.82% 41.97% 34.97% 5.65% 4.71% 3.77% 2.35% 0.75% 785.82% 42.12% 35.10% 5.65% 4.71% 3.77% 2.35% 0.47% 79 5.82% 42.12% 35.10%5.65% 4.71% 3.77% 2.35% 0.47% 80 5.82% 42.28% 35.23% 5.65% 4.71% 3.77%2.35% 0.19% 81 5.82% 43.15% 35.96% 5.65% 4.71% 1.88% 2.35% 0.47%

Dissolution Testing

Dissolution experiments were performed using 2-phase medium in a USPApparatus 2. The capsules were placed in stainless steel (316SS) wirespiral capsule sinkers for dissolution testing. The dissolutionparameters were as follows:

Dissolution medium: 750 ml 0.1N HCl for the first 2 hours; 250 ml 0.2 Mphosphate buffer was added to achieve a final pH of 6.8; Paddle speed:100 rpm; Vessel temperature: 37 C. Sampling time points: 0.25, 0.5, 1,2, 3, 6, 10, 12, 18 and 24 hours. Sampling volume: 1 mL.

The HPLC parameters were as follows: Mobile phase A: 0.5% sodium dodecylsulfate 1% glacial acetic acid, 20% acetonitrile; Mobile phase B: 100%acetonitrile; Mobile phase: 65% Mobile phase A and 35% Mobile phase B;240 nm wavelength. Capsule number=2-4 capsules per testing.

Abuse Deterrence

Capsules from each composition were tested for abuse deterrencecharacteristics. The release rate of hydromorphone HCl was determinedusing an isocratic HPLC method at defined time points. The capsules weresubjected to 60 mL of acidified 80-proof ethanol with vigorous shaking.Each capsule was placed in a wide mouth round jar containing 36 mL of0.1 N HCl and 24 mL 200-proof ethanol. The sample jar was placed in ashaking incubator maintained at 25° C. with 240 rpm shaking speed overthe course of the 3 hour extraction test. The sampling time points were0.5, 1, 2 and 3 hours. A 1 mL sample was taken at each time point andassayed using reverse-phase HPLC at 240 nm wavelength. The mobile phaseincluded 0.35% (w/v) SDS/0.7% (v/v) acetic acid/44% (v/v) acetonitrilein water.

Results

Dissolution Testing and Abuse Deterrence Results

The results of the dissolution and abuse deterrence experiments areprovided in Table 51 below.

TABLE 51 2-phase Dissolution %, %, %, %, %, %, %, %, %, %, %,Formulation 0.25 0.5 1 2 3 6 10 12 18 24 Abuse ID t = 0 hr hr hr hrs hrshrs hrs hrs hrs hrs at 3-hour 50 Mean 1 2 3 4 6 14 25 30 42 52 13 SD 1 11 2 2 5 8 10 11 12 51 Mean 0 1 1 2 2 2 3 3 4 5 15 SD 0 1 0 1 0 1 1 1 1 152 Mean 2 4 6 9 12 20 28 31 40 47 21 SD 1 1 1 1 1 2 4 4 5 7 53 Mean 0 11 1 2 2 3 3 4 5 16 SD 0 0 0 0 1 0 0 0 1 1 54 Mean 1 3 4 7 10 19 31 36 5061 17 SD 0 1 1 2 3 4 6 6 8 8 55 Mean 2 2 3 4 6 8 9 9 11 13 10 SD 0 1 0 12 1 1 2 2 3 56 Mean 2 3 3 4 8 11 15 17 24 29  9 SD 0 1 0 1 2 2 3 3 5 757 Mean 2 2 2 3 4 5 5 6 6 6  5 SD 0 0 0 0 1 1 1 1 1 1 58 Mean 2 2 2 2 45 5 5 5 5 19 SD 0 0 0 1 1 1 1 1 1 1 59 Mean 0 1 1 1 1 2 2 2 2 3 14 SD 00 0 0 0 1 0 0 1 1 60 Mean 0 1 1 2 2 3 4 4 5 6  7 SD 1 0 1 1 0 1 1 1 2 261 Mean 1 3 4 7 9 18 28 32 44 54 14 SD 1 1 1 1 2 3 4 5 6 7 62 Mean 0 0 12 2 3 5 6 8 10 15 SD 0 0 1 1 1 1 1 1 2 2 63 Mean 0 1 1 2 3 4 5 6 7 9 11SD 0 0 0 1 1 1 1 1 2 1 64 Mean 0 1 2 3 3 5 6 7 10 13 34 SD 0 0 0 1 1 1 22 2 3 65 Mean 1 5 10 18 25 45 62 68 83 93 30 SD 1 1 2 3 3 4 3 3 2 2 66Mean 0 1 2 2 3 6 11 14 23 32 19 SD 0 1 1 1 1 2 3 4 5 6 67 Mean 0 2 5 811 21 31 35 46 54 13 SD 0 1 1 2 3 4 6 6 7 7 68 Mean 0 0 1 1 2 3 5 6 9 1210 SD 0 0 1 1 0 0 1 1 1 2 69 Mean 0 0 1 2 2 4 5 6 8 10 12 SD 0 1 1 1 1 11 2 2 2 70 Mean 1 1 2 2 3 4 5 6 9 12 10 SD 1 0 1 1 0 1 1 1 1 2 71 Mean 00 2 2 3 5 7 8 12 16 14 SD 0 0 1 1 0 1 1 2 1 2 72 Mean 0 0 1 2 2 3 4 5 68 18 SD 0 0 1 1 1 1 1 2 2 2 73 Mean 0 1 1 2 2 4 6 7 10 12  9 SD 0 1 0 11 1 2 2 2 3 74 Mean 0 1 1 2 2 3 5 5 7 9 13 SD 0 1 1 1 1 1 1 2 2 2 75Mean 1 1 1 2 2 3 5 5 8 9 12 SD 1 0 1 1 1 1 2 2 2 2 76 Mean 1 1 2 3 4 5 77 10 12 13 SD 1 1 1 1 1 2 2 2 3 3 77 Mean 1 2 3 4 6 13 23 27 38 46 15 SD0 1 1 1 2 4 6 7 7 8 78 Mean 0 0 1 2 2 4 5 5 8 10 11 SD 0 0 1 0 1 1 1 1 11 79 Mean 0 0 1 1 2 2 4 4 6 7 15 SD 0 0 1 0 0 1 1 1 1 1 80 Mean 0 1 1 12 3 4 4 6 7 12 SD 0 1 0 1 1 1 1 1 2 2 81 Mean 0 0 1 1 1 2 3 3 4 5 13 SD0 1 0 0 1 1 1 1 1 1

No apparent phase separation was observed for the above formulations.With respect to dissolution characteristics, each of formulations 50,52, 54, 56, 61, 66, 67 and 77 exhibited dissolution profiles similar tothe initial release range of the targeted profile.

With respect to abuse deterrence, all formulations showed goodresistance to 40% ethanol extraction with the exception of 64 and 65which exhibited drug extraction of ≧30% after 3 hours.

Example 21: Preparation and Analysis of Extended Release HydrocodoneBitartrate Compositions (Formulations 82-95)

Hydrocodone bitartrate compositions were prepared and characterized withrespect to dissolution profile and abuse deterrence characteristics asindicated below.

Materials and Methods

The compositions were prepared to provide the compositions indicated inTable 52 below. Component amounts are % w/w relative to the total weightof the formulation including hydrocodone bitartrate prior toencapsulation, unless otherwise indicated. The SAIB/triacetin ratio isnoted.

The placebo formulations were prepared in 300 g scale. Formulations wereprepared as follows: several stock solutions, SAIB/TA at different ratioand 0.6% w/v BHT in IPM, were prepared before the compounding procedurestarted. The preparation took place in a 60° C.±5° C. water bath, andthe temperature was maintained at 60° C.±5° C. during the preparation.SAIB/TA stock solution was transferred into a jar, and 0.6% BHT in IPMsolution and the remaining IPM were added to the jar while mixing at 500rpm. This combination was then mixed uniformly. Cab-O-Sil®M-5P was addedand the combination was mixed for at least 2 hours. The mixture washomogenized at 9600 rpm for 5 minutes. Sieved CAB was then added intothe jar and dissolved in the content of the jar at the elevated speed.HEC was then added into the jar and dispersed. Part of the placebo wastransferred into a separate jar and hydrocodone bitartrate wasintroduced into the mixture and dispersed well to make 100 g activeformulations. The active formulations were filled into size 0 gelatincapsules.

TABLE 52 Formulation (containing 0.02% BHT) Formulation Dose (mg)/Gelucire ® ID Fill Weight (mg)/Conc. SAIB/TA SAIB Triacetin (TA) IPM CABCab-O-Sil ®M-5P HEC 50/13 82 75/550/13.64% 1.5 37.05 24.70 11.23 4.753.45 5.18 0 83 75/550/13.64% 1.5 38.08 25.39 11.23 3.02 3.45 5.18 0 8475/550/13.64% 1.5 35.49 23.66 13.82 4.75 3.45 5.18 0 85 75/550/13.64%1.3 34.66 26.66 13.82 3.45 2.59 5.18 0 86 75/550/13.64% 1.3 36.61 28.1611.23 5.18 2.59 0 2.59 87 75/550/13.64% 1.3 35.14 27.03 11.23 5.18 2.595.18 0 88 75/550/13.64% 1.3 33.68 25.91 13.82 5.18 2.59 5.18 0 8975/550/13.64% 1.5 38.34 25.56 13.82 3.45 2.59 0 2.59 90 75/550/13.64%1.5 38.86 25.91 11.23 5.18 2.59 0 2.59 91 75/550/13.64% 1.3 36.61 28.1611.23 3.45 1.73 5.18 0 92 75/550/13.64% 1.5 39.90 26.60 11.23 3.45 2.590 2.59 93 75/550/13.64% 1.3 37.10 28.54 11.23 5.18 1.73 0 2.59 9475/550/13.64% 1.5 38.34 25.56 11.23 3.45 2.59 5.18 0 95 75/550/13.64%1.4 36.77 26.27 12.52 4.32 2.59 2.59 1.30

Dissolution Testing

Dissolution experiments were performed using 2-phase medium in a USPApparatus 2. The capsules were placed in stainless steel (316SS) wirespiral capsule sinkers for dissolution testing. The dissolutionparameters were as follows: Dissolution medium: 750 ml 0.1N HCl for thefirst 2 hours; 250 ml 0.2 M phosphate buffer was added to achieve afinal pH of 6.8; Paddle speed: 100 rpm; Vessel temperature: 37 C.Sampling time points: 0.5, 2, 3, 6, 12, 18 and 24 hours. Samplingvolume: 1 mL.

The HPLC parameters were as follows: Mobile phase A: 0.5% sodium dodecylsulfatel % glacial acetic acid, 20% acetonitrile; Mobile phase B: 100%acetonitrile; Mobile phase: 65% Mobile phase A and 35% Mobile phase B;240 nm wavelength. Capsule number=2-4 capsules per testing.

Abuse Deterrence

Capsules from each composition were tested for abuse deterrencecharacteristics. The release rate of hydrocodone was determined using anisocratic HPLC method at defined time points. The capsules weresubjected to 60 mL of acidified 80-proof ethanol with vigorous shaking.Each capsule was placed in a wide mouth round jar containing 36 mL of0.1 N HCl and 24 mL 200-proof ethanol. The sample jar was placed in ashaking incubator maintained at 25° C. with 240 rpm shaking speed overthe course of the 3 hour extraction test. The sampling time points were0.5, 1 and 3 hours. A 1 mL sample was taken at each time point andassayed using reverse-phase HPLC at 240 nm wavelength. The mobile phaseincluded 0.35% (w/v) SDS/0.7% (v/v) acetic acid/47% (v/v) acetonitrilein water.

Results

Dissolution Testing and Abuse Deterrence Results

The results of the dissolution and abuse deterrence experiments areprovided in Tables 53 below.

TABLE 53 Dissolution Results (% Cumulative Drug Released), RM- 07-059 %,Cumulative 0.5 2 3 6 12 18 24 release after 3 Formulation ID hr hr hr hrhr hr hr hrs extraction 82 1 3 3 4 7.8 11 14 15 83 1 3 4 6 10 15 19 2084 1 2 3 5 9.8 15 21  9 85 0 3 4 7 16 24 30 18 86 27 54 62 78 94 97 9838 87 0 3 3 6 11 17 20 12 88 0 3 4 7 15 23 31 11 89 25 43 51 70 91 97 9949 90 22 46 55 71 90 96 98 34 91 2 4 4 8 16 23 30 17 92 24 45 53 70 8793 95 38 93 22 48 57 71 87 92 95 65 94 1 3 4 7 14 19 22 15 95 18 42 4963 81 89 93 37

Example 22: Preparation and Analysis of Extended Release AmphetamineCompositions (Formulations 96-100)

Amphetamine compositions were prepared and characterized with respect todissolution profile and abuse deterrence characteristics as indicatedbelow.

Materials and Methods

The compositions were prepared to provide the compositions indicated inTable 54 (below). Component amounts are % w/w relative to the totalweight of the formulation including amphetamine sulfate prior toencapsulation, unless otherwise indicated.

The placebo formulations were prepared in 150 g scale. Formulations wereprepared as follows: stock solutions, SAIB/TA at different ratio and0.6% w/v BHT in IPM, were prepared before the compounding procedurestarted. The preparation took place in a 60° C.±5° C. water bath, andthe temperature was maintained at 60° C.±5° C. during the preparation.SAIB/TA stock solution was transferred into a jar. Sieved CAB was addedinto the jar and dispersed and dissolved in the solution at an elevatedspeed. 0.6% BHT in IPM and IPM was added to the jar and mixed uniformly.Gelucire® 50/13 was added to the content in the jar and mixed uniformly.Cab-O-Sil®M-5P was added and mixed to disperse uniformly. Part of theplacebo was transferred into a separate jar and amphetamine sulfate wasintroduced into the mixture and dispersed well to make 100 g activeformulations. The active formulations were filled into size 0 gelatincapsules.

TABLE 54 Formulation (containing 0.02% BHT) Cab-O-Sil ® FormulationD-Amp SAIB/ SAIB Triacetin IPM CAB HEC M-5P Gelucire ® ID API Conc. %Triacetin % % % % % % 50/13, % 96 D-Amphetamine 5.45 1.35 38.97 28.87 9.46 4.96 5.67 1.89 4.73 Sulfate 97 D-Amphetamine 5.45 1.35 38.43 28.47 9.46 5.91 5.67 1.89 4.73 Sulfate 98 D-Amphetamine 5.45 1.35 42.77 31.68 9.46 5.91 0.00 0.00 4.73 Sulfate 99 D-Amphetamine 5.45 1.35 38.16 28.2616.07 4.96 0.00 2.36 4.73 Sulfate 100  D-Amphetamine 5.45 1.35 37.8928.06 16.07 4.96 0.00 2.84 4.73 Sulfate

Dissolution Testing

2-phase dissolution medium was utilized in a USP Apparatus 2. Capsuleswere placed in stainless steel (316SS) wire spiral capsule sinkers fordissolution testing. The dissolution parameters were as follows:Dissolution medium: 750 ml 0.1N HCl for the first 2 hours, followed bythe addition of 200 ml 0.19M phosphate buffer to achieve a final pH of6.0; Paddle speed: 50 rpm; Vessel temperature: 37° C. Sampling timepoints: 0.25, 0.5, 1, 1.5, 2, 3, 6, 9, 12 and 24 hours. Sampling volume:1 mL. HPLC parameters were as follows: Mobile phase A: 5 mM1-Decanesulfonic acid, sodium salt, 5 mM sodium phosphate monobasic, pH2.5; Mobile phase B: 100% acetonitrile; Mobile phase: 67% Mobile phase Aand 33% Mobile phase B; 210 nm wavelength. Capsule number=4 capsules pertest.

Abuse Deterrence

Capsules from each composition were tested for abuse deterrencecharacteristics. The release rate of dextroamphetamine was determinedusing an isocratic HPLC method at defined time points. The capsules weresubjected to 60 mL of acidified 80-proof ethanol with vigorous shaking.Each capsule was placed in a wide mouth round jar containing 36 mL of0.1 N HCl and 24 mL 200-proof of ethanol. The sample jar was placed in ashaking incubator maintained at 25° C. with 240 rpm shaking speed overthe course of the 3 hour extraction test. The sampling time points were0.5 and 3 hours. A 1 mL sample was taken at each time point and assayedusing reverse-phase HPLC at 210 nm wavelength. The mobile phase includedand 33% (v/v) acetonitrile in 67% (v/v) 5 mM 1-Decanesulfonic Acid, Nasalt, 5 mM sodium phosphate, pH 2.5.

Results

Dissolution Testing and Abuse Deterrence Results

The results of the dissolution and abuse deterrence experiments areprovided in Tables 55-59 and 60 respectively below.

TABLE 55 Formulation 96 D-Amphetamine % Cumulative drug released (%)Dissolution Sulfate (mg) 1 hr 2 hr 3 hr 6 hr 8 hr 10 hr 12 hr 18 hr 24hr #1 15.18 44.45 63.27 73.77 90.63 96.43 99.14 100.27 100.65 100.71 #214.91 42.75 59.03 67.82 84.87 91.81 95.78 97.92 98.54 98.79 #3 15.8946.80 64.48 73.97 91.33 97.95 101.67 103.18 104.06 103.87 #4 15.34 44.4060.43 70.29 87.97 94.09 98.12 99.82 100.64 101.14 Average 15.3 44.6 61.8  71.5  88.7  95.1  98.7 100.3 101.0 101.1 Std Dev 0.4 1.7 2.5 3.02.9 2.7 2.4 2.2 2.3 2.1 % RSD 2.7 3.7 4.1 4.1 3.3 2.8 2.5 2.2 2.3 2.1

TABLE 56 Formulation 97 D-Amphetamine % Cumulative drug released (%)Dissolution Sulfate (mg) 1 hr 2 hr 3 hr 6 hr 8 hr 10 hr 12 hr 18 hr 24hr #1 14.68 39.40 55.03 64.15 81.19 88.38 92.48 94.74 96.19 97.32 #215.99 42.85 59.48 69.28 86.95 94.59 98.55 101.07 102.71 103.71 #3 15.8839.95 57.18 67.37 85.81 93.44 97.85 100.81 102.57 103.57 #4 15.82 35.4551.68 61.80 80.80 88.94 94.23 98.01 101.78 102.59 Average 15.6  39.4 55.8  65.6  83.7  91.3  95.8  98.7 100.8 101.8 Std Dev 0.6 3.0 3.3 3.33.1 3.1 2.9 3.0 3.1 3.0 % RSD 3.9 7.7 5.9 5.1 3.8 3.4 3.0 3.0 3.1 3.0

TABLE 57 Formulation 98 D-Amphetamine % Cumulative drug released (%)Dissolution Sulfate (mg) 1 hr 2 hr 3 hr 6 hr 8 hr 10 hr 12 hr 18 hr 24hr #1 14.73 0.00 2.35 2.97 4.87 6.00 7.20 8.65 13.36 17.88 #2 14.78 0.000.00 2.53 4.11 5.87 7.07 7.57 10.97 14.74 #3 14.73 0.00 3.05 3.23 4.685.94 7.01 8.33 12.11 15.75 #4 14.84 0.00 0.00 2.78 4.67 6.06 7.70 9.4014.43 19.33 Average 14.8  0.0 1.3 2.9 4.6 6.0 7.2 8.5 12.7 16.9 Std Dev0.1 0.0 1.6 0.3 0.3 0.1 0.3 0.8 1.5 2.1 % RSD 0.4 NA 117.4 10.3 7.2 1.44.3 8.9 11.8 12.2

TABLE 58 Formulation 99 D-Amphetamine % Cumulative drug released (%)Dissolution Sulfate (mg) 0.25 hr 0.5 hr 1 hr 1.5 hr 2 hr 3 hr 6 hr 9 hr12 hr 24 hr #1 14.62 20.00 33.13 50.74 63.09 71.94 82.41 94.37 96.0696.63 97.99 #2 15.00 19.40 34.33 50.89 61.84 70.15 80.64 94.93 97.4497.88 99.05 #3 15.44 21.60 38.23 55.18 66.19 74.39 84.95 98.67 100.81101.37 102.42 #4 14.84 23.45 38.28 54.24 64.65 72.35 82.30 95.33 97.6598.03 99.39 Average 15.0  20.3  35.2  52.3  63.7  72.2  82.7  96.0  98.198.6 99.8 Std Dev 0.3 1.1 2.7 2.5 2.2 2.1 2.2 2.3 2.4 2.5 2.3 % RSD 2.35.6 7.6 4.8 3.5 3.0 2.6 2.4 2.5 2.5 2.3

TABLE 59 Formulation 100 D-Amphetamine % Cumulative drug released (%)Dissolution Sulfate (mg) 0.25 hr 0.5 hr 1 hr 1.5 hr 2 hr 3 hr 6 hr 9 hr12 hr 24 hr #1 14.68 18.75 34.93 51.33 62.09 69.55 79.51 93.86 96.6297.44 99.11 #2 15.34 20.50 38.18 56.28 67.53 75.64 85.33 97.92 100.06100.94 102.23 #3 14.79 21.50 35.08 51.39 62.15 70.55 80.21 94.43 96.8297.26 98.93 #4 14.36 18.80 32.08 49.34 60.74 69.05 78.49 91.27 93.2893.78 95.39 Average 14.8  20.3  36.1  53.0  63.9  71.9  81.7  95.4  97.898.5 100.1 Std Dev 0.4 1.4 1.8 2.8 3.1 3.3 3.2 2.2 1.9 2.1 1.9 % RSD 2.86.9 5.1 5.4 4.9 4.5 3.9 2.3 2.0 2.1 1.9

TABLE 60 %, Cumulative release Formulation ID after 3 hrs extraction 9655 97 55 98 44 99 54 100 52

Example 23: Preparation and Analysis of Additional Extended ReleaseOxycodone Compositions (Formulations 101-104)

Oxycodone compositions were prepared and characterized with respect toappearance as indicated below.

Materials and Methods

The compositions were prepared to provide the compositions indicated inTable 61 (below). Formulation 103 was prepared as follows:SAIB/IPM/Ethyl Lactate (EL)=65/3/27 stock solution was prepared.Approximately 19 g of SAIB/IPM/EL solution was weighed and mix with 0.1g of Tween 20 and 1 g of SiO₂ to make placebo Formulation 103. 1.147 gof oxycodone base was added to placebo Formulation 103 to produce 54.06mg/g Formulation 103. Formulation 103 was then filled into hard gelatincapsule size 00 with approximately 780 mg fill weight for testing.

Stock solution C, SAIB/IPM=65/3, was prepared to make Formulation 104.Stock solution C was made by weighing out approximately 260 grams ofSAIB and mixing with 12 grams of IPM. To make formulation 104,CA/SAIB/IPM/SiO₂, 5/65/3/2.5, placebo 101 (Formulation 101 withoutoxycodone) and placebo 102 (Formulation 102 without oxycodone) were madeseparately. Placebo 101 was prepared by mixing 13.6 grams of stocksolution C with 2 gram of SiO₂ and placebo 102 was prepared by mixing13.6 grams of stock solution C and 2 grams of cellulose acetate (CA).3.16 grams of placebo 101 SiO₂/SAIB/IPM, 5/65/3 and 3.16 grams ofplacebo 102 CA/SAIB/IPM, 10/65/3 were mixed at a 50:50 ratio to makeplacebo 104. 0.351 grams of oxycodone base was added to placebo 104 toproduce 52.29 mg/g formulation 104. Formulations were then filled intogelatin capsule size 00 with approximately 780 mg fill weight andobserved with respect to appearance.

Results

The results with respect to appearance are provided in Table 61 below.

TABLE 61 Appearance after addition Appearance of SAIB (& of Polymer inrheology Solvent 1 (or modifier) (or Appearance Formulation RheologyOther of initial of final of Mass in ID Polymer Solvent SAIB Modifierexcipients mixture) mixture) EtOH/water 101 6.85% Cabosil — 89.04% 4.11%oxycodone NA viscous gel −> oil-like drops M-5 IPM suspension andsand-like after particles in compounding milky soln after 3.5 hours 10212.82% CA- — 83.33% 3.85% oxycodone NA viscous oil-like drops 398-10NFIPM suspension and sand-like particles in milky soln after 3.5 hours 1034.98% Cabosil 26.87% 64.68% 2.99% 0.5% Tween-20 + oxycodone in addCabosil −> oil-like M-5 EL IPM oxycodone all viscous paste droplets insolvents/SAIB −> opaque suspension solution after 3.5 hours 104 3.42% —89.04% 4.11% oxycodone mix 101 and add oxycodone −> oil-like Cabosil/IPM 102 placebos −> viscous droplets in 3.42% CA- viscous pasty opaque398-10NF suspension suspension solution after 3.5 hours

Example 24: Preparation and Analysis of Additional Extended ReleaseOxycodone Composition (Formulations 105)

Oxycodone compositions were prepared and characterized with respect todissolution and abuse deterrence characteristics as indicated below.

Materials and Methods

The compositions were prepared to provide the compositions indicated inTable 62 below. Component amounts are % w/w relative to the total weightof the formulation including oxycodone base prior to encapsulation,unless otherwise indicated.

The placebo formulations were prepared in 500 g scale. A stock solution,SAIB/TA (1.35), was prepared before the compounding procedure started.The preparation took place in a 60° C.±5° C. water bath. SAIB/TA (1.35)was transferred into a jar, and BHT was added to the solution whilemixing at 500 rpm. Then CAB was added to the solution, and mixed@1500RPM until all the particles were dissolved. IPM was added to themixture and dispersed uniformly, and then HEC was added into the jar andmixed for 30 minutes. Cab-O-Sil®M-5P particles were added to the mixtureand were dispersed uniformly. Part of the placebo formulation wastransferred into a separate jar and oxycodone base was introduced intothe mixture and dispersed well to make 100 g active formulations. Activeformulations were filled into size 00 gelatin capsules.

TABLE 62 Dose/Fill Formulation Composition (with 0.02% BHT) FormulationWt SAIB/TA Oxycodone SAIB Triacetin IPM CAB HEC Cab-O-Sil ®M-5P ID #(mg/mg) Ratio % % (TA) % % % % % 105 80/780 1.35 10.26 35.44 26.26 15.264.71 5.38 2.69

Dissolution Testing

Dissolution experiments were performed using 2-phase medium in a USPApparatus 2. The capsules were placed in stainless steel (316SS) wirespiral capsule sinkers for dissolution testing. The dissolutionparameters were as follows: Dissolution medium: 750 ml 0.1N HCl for thefirst 2 hours, add 250 ml 0.2 M phosphate buffer to achieve a final pHof 6.8; Paddle speed: 100 rpm; Vessel temperature: 37 C. Sampling timepoints: 0.25, 0.5, 1, 2, 3, 6, 10, 12, 18 and 24 hours. Sampling volume:1 mL.

The HPLC parameters were as follows: Mobile phase A: 0.5% sodium dodecylsulfatel % glacial acetic acid, 20% acetonitrile; Mobile phase B: 100%acetonitrile; Mobile phase: 65% Mobile phase A and 35% Mobile phase B;240 nm wavelength. Capsule number=2-4 capsules per testing.

Abuse Deterrence

Capsules from each composition were tested for abuse deterrencecharacteristics. The release rate of oxycodone was determined using anisocratic HPLC method at defined time points. The capsules weresubjected to 60 mL of acidified 80-proof ethanol with vigorous shaking.Each capsule was placed in a wide mouth round jar containing 36 mL of0.1 N HCl and 24 mL 200-proof of ethanol. The sample jar was placed in ashaking incubator maintained at 25° C. with 240 rpm shaking speed overthe course of the 3 hour extraction test. The sampling time points were0.5, 1, and 3 hours. A 1 mL sample was taken at each time point andassayed using reverse-phase HPLC at 240 nm wavelength. The mobile phaseincluded 0.35% (w/v) SDS/0.7% (v/v) acetic acid/44% (v/v) acetonitrilein water.

Results

Dissolution Testing and Abuse Deterrence Results

The results of the dissolution and abuse deterrence experiments areprovided in Table 63 below.

TABLE 63 %, Cumulative Dissolution (TM-254B) release after 3 FormulationDose/Fill Wt % % % % % % hrs extraction ID # (mg/mg) 0.5 hr 3 hr 6 hr 10hr 12 hr 24 hr (TM-256) 105 80/780 7 24 40 68 85 95 44

Example 25: Capsule Shell Interaction Study

The formulations indicated in Table 64 were prepared and filled intoeither hard gelatin or HPMC capsules to evaluate the effect of capsulechoice on dissolution and storage time dependent change in mean releaseof active agent. The Formulation 106 placebo was prepared at 1 kg scaleusing an overhead mixer. A Sucrose Acetate Isobutyrate(SAIB)/Triacetin(TA)=1.5 stock solution was prepared prior to thecompounding process, and the temperature of the process was maintainedat 60° C.±5° C. throughout. SAIB/TA (1.50) stock solution was added to aglass jar, and placed into the water bath. Isopropyl Myristate (IPM) wasadded, and mixed at 600 rpm. Colloidal silicon dioxide (Cab-O-Sil) wasadded to the solution mixed for 20 minutes. The mixture was homogenizedusing Fisher PowerGen 500 with a setting of 9600 rpm for 5 minutes.Sieved cellulose acetate butyrate (CAB) was added to the jar whilemixing at 1000 rpm followed by 1430 rpm for 35 minutes. Finally, sievedhydroxyethyl cellulose (HEC) was added into the jar and mixed for 30minutes to complete the formulation. The active formulation was preparedin 250 g scale. For Formulation 106, approximately 13 grams of oxycodonebase was weighed out and mixed with 240 gram of placebo formulation in aseparate bottle until uniform. The Formulation 107 placebo was preparedsimilarly to the above with the exception of adding Gelucire 44/14 inthe formulation. For Formulation 107, approximately 27 grams ofoxycodone base was weighed out and mixed with 236 gram of placeboformulation in a separate bottle until uniform.

Placebo and active formulations were manually filled into white opaquehard gelatin capsules (Capsugel Licap size 0) with filling weight of 585mg. The same fill weight was filled into white HPMC capsules (QualicapsQuali-V size 0). For Formulation 106, 30 mg capsules were made. ForFormulation 107, 60 mg capsules were made.

TABLE 64 Formulation Formulation 106 107 30 mg 60 mg Component % Weight% Weight Oxycodone Base 5.13 10.26 SAIB 40.98 35.87 Triacetin 27.3226.57 IPM 14.23 14.36 CAB 4.74 4.94 HEC 5.69 4.49 Cab-O-Sil 1.90 2.15BHT 0.02 0.02 Gelucire 44/14 — 1.35

In addition, the water content of the empty capsules was determined byKarl Fischer titration generally as set forth in USP <921> Method 1Cusing an AquaStar C3000 Karl Fischer Coulometric Titrator. The resultsof the Karl Fischer titration showing the difference in water contentbetween the empty gelatin and HPMC capsules are provided below in Table65.

TABLE 65 Sample W. (mg) Ave. Stdev % CV Licaps ® Gelatin 94.44 15.280.02 0.1 Capules 95.30 14.86 0.07 0.5 97.91 15.44 0.11 0.7 Grand = 15.190.30 2.0 Quali-V ® HPMC 92.30 4.72 0.03 0.6 Capules 96.60 4.72 0.15 3.2Grand = 4.72 0.00 0.1

The release rate of oxycodone base was determined from six capsulesusing a USP Apparatus 2 dissolution tester. Dissolution mediumcontaining 1000 ml 0.1 N HCl with 0.5% (w/w) SDS was maintained at 37°C. with 100 rpm paddle speed over the course of the 24 hour dissolutiontest. A 20 mesh screen hanging basket was incorporated to hold the testarticle. The standard sampling time points were 0.5, 2, 3, 6, 12, 18 and24 hours. A 1 mL sample was taken at each time point and assayed usingreverse-phase HPLC at 240 nm wavelength. The mobile phase included 0.35%(w/v) SDS/0.7% (v/v) acetic acid/44% (v/v) acetonitrile in water.

The initial dissolution results at T=0 for Formulations 106 and 107 ingelatin and HPMC capsules are provided in FIG. 44. FIG. 45 shows astorage time-dependent change in mean release of the active agent forFormulation 106 in gelatin capsules when stored for 1 month at 25° C.and 40° C., or for 30 months at 25° C. As shown in FIG. 46, Formulation106 exhibited greater stability in HPMC capsules as evidenced by adecrease in the storage time-dependent change in mean release of theactive agent. FIG. 47 shows dissolution results for Formulation 107 ingelatin capsules when stored for 1 month at 25° C. and 40° C., or for 30months at 25° C. FIG. 48 shows dissolution results for Formulation 107in HPMC capsules when stored for 1 month at 25° C. and 40° C., or for 30months at 25° C. Formulation 107 exhibited good stability in bothgelatin and HPMC capsules as evidenced by the absence of a significantstorage time-dependent change in mean release of the active agent.Without intending to be bound by any particular theory, it appears thatFormulation 106 filled in hard gelatin capsules showed dissolutionchanges due to potential interaction between the capsule and theformulation. Formulation 107 showed good product stability withoutdissolution change in both types of capsule shell.

What is claimed is:
 1. A method for administering a pharmacologicallyactive agent to a subject, the method comprising: orally administeringto the subject a composition comprising: a pharmacologically activeagent; a high viscosity liquid carrier material (HVLCM) having aviscosity of at least 5000 cP at 37° C. that does not crystallize neatat 25° C. and 1 atmosphere; a solvent; a network former; water; and amineral particle, wherein the mineral particle is present in thecomposition in an amount from 2.4% by weight to about 5.4% by weightrelative to the total weight of the composition, wherein the compositiondoes not comprise more than 2.0% water by weight, based on total weightof the composition.
 2. The method of claim 1, wherein the mineralparticle comprises silicon dioxide.
 3. The method of claim 1, whereinthe pharmacologically active agent is selected from opioid, stimulant,and depressant.
 4. The method of claim 1, wherein the pharmacologicallyactive agent is an opioid.
 5. The method of claim 1, wherein thepharmacologically active agent is selected from oxycodone, oxymorphone,hydrocodone, and hydromorphone, either in free base form or apharmaceutically acceptable salt form thereof.
 6. The method of claim 1,wherein the pharmacologically active agent is oxycodone, and wherein themethod comprises treating pain in the subject.
 7. The method of claim 1,wherein the HVLCM is sucrose acetate isobutyrate (SAIB).
 8. The methodof claim 1, wherein the composition comprises about 35% by weight toabout 45% by weight of the HVLCM relative to the total weight of thecomposition.
 9. The method of claim 1, wherein the solvent comprisestriacetin.
 10. The method of claim 1, wherein the composition comprisesabout 31% by weight to about 45% by weight of the solvent relative tothe total weight of the composition.
 11. The method of claim 1, whereinthe composition further comprises a rheology modifier.
 12. The method ofclaim 11, wherein the rheology modifier is isopropyl myristate (IPM).13. The method of claim 11, wherein the composition comprises about 2%by weight to about 10% by weight of the rheology modifier relative tothe total weight of the composition.
 14. The method of claim 1, whereinthe network former comprises cellulose acetate butyrate (CAB).
 15. Themethod of claim 14, wherein the CAB has a number average molecularweight ranging from 50,000 Daltons to 100,000 Daltons.
 16. The method ofclaim 14, wherein the CAB has at least one feature selected from abutyryl content ranging from about 17% to about 41%, an acetyl contentranging from about 13% to about 30%, and a hydroxyl content ranging fromabout 0.5% to about 1.7%.
 17. The method of claim 1, wherein thecomposition further comprises a hydrophilic agent.
 18. The method ofclaim 17, wherein the hydrophilic agent comprises HEC.
 19. The method ofclaim 1, wherein the mineral particle is present in the composition inan amount from about 2.5% by weight to about 3.0% by weight relative tothe total weight of the composition.
 20. The method of claim 1, whereinthe composition is contained within a capsule.
 21. The method of claim1, wherein the composition is contained within a capsule having a watercontent of less than about 10% by weight.
 22. The method of claim 1,wherein the composition is contained within a capsule comprisinghydroxypropyl methylcellulose.
 23. The method of claim 1, wherein thecomposition comprises water at from about 1.0 to 2.0% by weight, basedon total weight of the composition.
 24. The method of claim 1, whereinthe composition does not comprise more than 2.0% water by weight, basedon total weight of the composition, following storage of the compositionfor a period of 12 months at 25° C. and 60% relative humidity.
 25. Themethod of claim 1, wherein the composition comprises water at from about1.0 to about 2.0% by weight, based on total weight of the composition,following storage of the composition for a period of 12 months at 25° C.and 60% relative humidity.